Beyond the boundaries of cardiology: Still untapped anticancer properties of the cardiovascular system-related drugs

Accepted Manuscript Title: Beyond the boundaries of cardiology: still untapped anticancer properties of the cardiovascular system-related drugs Authors: Katarzyna Regulska, Miłosz Regulski, Bartosz Karolak, Marcin Michalak, Marek Murias, Beata Stanisz PII: DOI: Article Number:

S1043-6618(19)30352-4 https://doi.org/10.1016/j.phrs.2019.104326 104326

Reference:

YPHRS 104326

To appear in:

Pharmacological Research

Received date: Revised date: Accepted date:

24 February 2019 18 June 2019 21 June 2019

Please cite this article as: Regulska K, Regulski M, Karolak B, Michalak M, Murias M, Stanisz B, Beyond the boundaries of cardiology: still untapped anticancer properties of the cardiovascular system-related drugs, Pharmacological Research (2019), https://doi.org/10.1016/j.phrs.2019.104326 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Beyond the boundaries of cardiology: still untapped anticancer properties of the cardiovascular system-related drugs

Katarzyna Regulska1*, Miłosz Regulski2, Bartosz Karolak3, Marcin Michalak4, Marek Murias5, Beata Stanisz6* Greater Poland Oncology Center, Hospital Pharmacy, 15 Garbary Street, 61-866 Poznań, Poland, email: [email protected], phone: 48618850704 2 Masters Ltd, Wysogotowo, 30 Skórzewska Street, 62-081 Przeźmierowo, Poland 3 Department of Internal Medicine and Cardiology with the Centre of Management of Venous Thromboembolic Disease, Infant Jesus Teaching Hospital, Lindleya 4 Street, 02-005 Warsaw, Poland 4 Radiotherapy and Gynaecological Oncology Department, Greater Poland Oncology Center, 15 Garbary Street, 61-866 Poznań, Poland 5 Poznan University of Medical Sciences, Chair and Department of Toxicology, 30 Dojazd Street, 60-631 Poznan, Poland 6 Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 6 Grunwaldzka Street, 60-780 Poznan, Poland, email: [email protected], phone: 48618546650

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Graphical abstract

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Abstract Cardiovascular disorders and cancer are the most common chronic diseases, frequently coexistent and interdependent. Based on their common etiology and molecular background, the hypothesis on the potential anti-cancer activity of cardiological drugs appeared, mainly in response to the necessity of increasing the efficacy of existing oncological treatment schemes. In fact, cancer is known to induce the profound malfunction of typical cardiovascular-regulating systems, including the renin-angiotensin system, sympathetic nervous system and coagulation cascade. Therefore, in this review we have analyzed the available preclinical and clinical data on the repurposing potential of the following classes of cardiology drugs: angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, beta blockers, statins and heparins. All of them have been shown to attenuate cancer development: the renin-angiotensin system inhibitors primarily by reducing inflammation, angiogenesis and immunosuppression, beta blockers by repressing migration and metastasis, heparins by decreasing metastasis and statins by influencing cell growth, apoptosis, migration and angiogenesis. We also have discussed the specific mechanisms of anticancer action for each group and then suggestions on their potential clinical use have been presented. Nonetheless, the establishment of strong indications for repurposing procedure, both individually and collectively, is unfeasible at the moment due to insufficient clinical data and therefore further investigations in this context are necessary and encouraged.

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Key words: carcinogenesis, drug repurposing, cardiology, oncology, chemoprevention, adjuvant treatment

1. Introduction

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According to the WHO, almost 70% of cancer deaths occur in developing world regions, where the expected mortality rate is going to rise drastically over the next ten years. The incrasing cancer burden in low- and middle-income countries results mainly from limited financial resources and insufficient capacity for cancer care, including inadequate or no prevention strategies, limied access to timely diagnosis and unavailability of effective treatment methods [1]. Thus, the unmet need for effective, low-cost and widely-available anticancer drugs, not only in developing countries but also in advanced world regions, has prompted the search for cheaper adjuvant strategies through the repositioning path. In fact, drug repurposing or repositioning is an alternative to drug research and development, refering to the application of an approved drug in new indiations. It is a well-established, time-sparing and cost-effective strategy that has already led to introducing aspirin and celecoxib into the prophylaxis of colorectal cancer (CRC) as well as thalidomide into the treatment of multiple myeloma [2]. Furtherore, the intense research on cancer biology has provided additional clues also for cardiovascular drugs repurposing, based on the dependency of cancer progression on structural and functional disorders of several host innate mechanisms regulating cardiovascular homeostasis. Consistently with this, it is believed that cancer for survial reasons develops various adaptation mechanisms to reprogram the renin-angiotensin system (RAAS), the sympathetic nervous system (SNS), the cyclooxygenase system (COX) and the coagulation system [2–5] so that they operate to its advantage by increasing proliferation, reducing apoptosis, supporting migration metastasis and angiogenesis. Therefore, the corresponding cardiology drugs, by normalizing the dysregulated cardiovascular functions, have the potential to delay or suppress cancer progression [6]. The available pre-clinical and clinical data seem to support this concept and thus, this review will focus on the reported anticancer properties of five classes of agents, i.e.: angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta blockers (BBs), statins, heparin and low molecular weight heparins (LMWH). They will be discussed in descending order from the most probable to the least likely in the context of repositioning to oncological indications. Of note, cardiac glycosides and calcium channel blockers have also been investigated with this aim, however they remained beyond scope of current discussion due to more speculative and less convincing character of the available data for them [7,8]. 2. RAAS, Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

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Of the aforementioned, the largest amount of experimental data in the context of repositioning to oncology is available for drugs modulating RAAS activity. RAAS is a hormone-enzyme system regulating a variety of body functions through either endocrine or paracrine mechanism. The systemic/endocrine RAAS is responsible for the maintenance of blood pressure, cardiovascular homeostasis and fluid and electrolyte balance, which justifies its targeting in cardiovascular diseases. Besides, local/paracrine RAAS expressed in many tissues, controls functions of host organs (including brain, adrenal glands, ovaries, testes, heart, peripheral blood vessels, kidney, adipose tissue and pancreas) regulating basic cellular processes, such as.: proliferation, apoptosis, migration, angiogenesis, etc. The local RAAS can act independently or interdependently of the systemic RAAS. The main effector molecule of RAAS, angiotensin II (ANG II) is cleaved from angiotensin I by angiotensin-converting enzyme (ACE). ANG I, in turn, is produced from clevage of angiotensinogen 3

2.1. The abnormal expression of RAAS components in neoplasia

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catalyzed by renin [9]. ANG II exerts stimulatory or inhibitory effects depending on which angiotensin receptor (AT1R or AT2R) is activated. AT1R is the main mediator of physiological actions of ANG II, inducing vasoconstriction, water and sodium reabsorption, increase in blood preassure (for systemic RAAS), proliferation, angiogenesis, inflammation and inhibition of apoptosis (for tissue RAAS). AT2R, in turn, appears to have the inhibitory influence on the events induced by AT1R yet its expression in adult humans is minor. In addition, alternative enzyme-hormone-receptor axes exist within RAAS to provide its self-regulation [3]. The best recognized of these is the angiotensinconverting enzyme type 2/angiotensin(1-7)/mitochondrial assembly receptor (ACE-2/ANG 1-7/MASR) axis, opposing the effects of ACE/ANGII/AT1 pathway [10]. Based the capability of ACE/ANGII/AT1 axis to increase blood pressure, RAAS inhibition has been one of the most important pharmacological targets in the management of cardiovascular and renal-related diseases for more than thirty years [11]. Furthermore, the involvement of tissue system in the stimulation of cellular processes underlying carcinogenesis indicates that the activity of the RAAS-inhibiting agents, including ACE-Is and ARBs, maight represent a potential therapeutic opportunity for clinical intervention in oncology [3].

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The implementation of ACE-Is and ARBs into anticancer strategies is mainly justified by the sustained overactivation of the stimulatory arm of RAAS (i.e. ACE/ANG II/ AT1) in the variety of neoplasms. The pathophysiological consequences of this anomaly generally involve the amplification of proproliferatory, proangiogenic, proinflammatory and antiapoptotic cellular responses in both, cancer cells and their environment. For instance, increased content of AT1R and downregulation of AT2R was confirmed in: squamous cell carcinoma of the skin, pancreatic cancer, hormone-refractory prostate cancer, myeloma, laryngeal and renal cell cancer (RCC) [3]. Additionally, various forms of cancer such as gastric, ovarian and cervical cancer havce increased AT1R density which is associated with tumor invasiveness and poor patient outcomes [12,13]. By contrast, the overstimulation of the inhibitory arm of RAAS with AT2R caused progression of CRC, suggesting that the profile of the malignancy-RAS-related interactions is heterogenous and tumor-specific [3,14]. In breast cancer, in turn, precursor lesions were shown to have enhanced level of AT1R and decreased level of AT2R, while in the invasive stage the concentration of AT1R decreased and AT2R raised. Additionally, in invasive breast ductal carcinoma, attenuated expression of MASR was reported [15]. As for ACE, its upregulation was observed in: CRC and its liver metastases [16], benign prostate hyperplasia, hormone-refractory prostate cancer, vascular and gastric tumors [17]. Similarly, in hematological malignancies the increased expression of ACE was confirmed, specifically in leukemic blast cells, erythroleukemic cells, multiple myeloma cells and macrophages in lymph nodes of Hodgkin disease [18]. Additionally, increased ACE activity, resulting from the insertion (I) /deletion (D) polymorphism of ACE-gene, was found to serve as a risk factor of benign prostatic hyperplasia and prostate cancer, as well as a negative prognostic factor of gastric cancer [17,19]. In endometrial cancer, in turn, it was the genotype associated with decreased ACE level, that predisposed to the disease development, confirming the complexity of the RAAS-driven procarcinogenic effects [3]. 2.3. The impact of RAAS malfunction on carcinogenesis Abnormal local expression of RAAS components in the neoplastic environment is thought to underlay the contribution of this system to carcinogenesis, physiologically manifested by the following malfunctions: stimulation of cell proliferation, protection from apoptosis, facilitation of 4

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migration and angiogenesis, generation of oxidative stress, maintenance of inflammation, acceleration of cachexia and immunosuppression, as depicted in Fig. 1. In the specific cancer context, however, the above mechanisms may occur individually, concurrently, consecutively or interdependently, meaning that the final effect of RAAS dysregulation differs for different types of malignancy [14]. Firstly, RAAS can induce or attenuate proliferation relying on whether AT1R or AT2R is activated. In this respect, the stimulatory arm, comprising ACE/ANG II/AT1R, was shown to activate the growth-factor-like cell responses in neoplastic and stromal cells via PI3K/Akt pathway or by the transactivation of epidermal growth factor receptor (EGFR) with the subsequent downstream ERK1/2, STAT3 and protein kinase C (PKC) signaling, observed particularly in prostate and breast cancer cells [3,20]. Besides, AT1R-related transduction was found to promote antiapoptotic actions in cancer through at least two distinct mechanisms. One of them, seen in choriocarcinoma and breast cancer [15], involved inducement of PI3K/Akt and abolishment of caspase 9. The other one was found in colon cancer, in which induction of nuclear factor-κB (NF-κB) and increased concentration of antiapoptotic BCL-XL and survivin occurred [21]. Increased cell migration and metastasis are another aspects of carcinogenesis driven by RAAS dysfunction. These effects were particularly confirmed in experimental models of lung metastases, where suppression of RAAS reduced the number and size of secondary lesions [14]. Similarly, in gastric cancer, excessive local production of ANG II caused the disease progression and the lymph node spread. At the molecular level, the alleged pathway responsible for the RAAS-mediated neoplastic migration could involve ANG II/AT1R/PI3K, as evidenced in choriocarcinoma [3]. Furthermore, in breast cancer, excess of ANG II augmented the metastatic process by increasing the adhesion of tumor cells to endothelium, followed by stimulation of their migration across endothelial barrier and final establishment of metastatic foci at secondary sites. These effects were accompanied by upregulation of genes encoding mitogen-activated protein kinases (MAPK), matrix metalloproteases (MMP-2, MMP-9) and adhesion molecules [22]. Compelling experimental evidence also provides support to the association between RAAS and neoplastic angiogenesis, inflammation, and immunosuppression, probably as a combined major procarcinogenic mechanism, shown in Fig. 1. In this regard, it was confirmed that overexpression of AT1R correlated with the production of vascular endothelial growth factor (VEGF), VEGF receptor distribution, higher microvessel density and increased tumor mass in the following cancer types: ovarian [23], breast, bladder [24], gastric [3] and pancreatic [25]. Interestingly, counterregulatory axes of RAAS opposed these effects, as AT2R activation was able to repress VEGF signaling and impair endothelial cells migration via two distinctive pathways: EGFR trans-inactivation with downstream ERK 1/2 attenuation as well as by suppression of VEGFR2-dependent phosphorylation of kinase Akt and endothelial nitric oxide synthase (eNOS) [3,14]. Likewise, MASR/ANG(1-7) arm caused VEGF inhibition, leading to decreased microvessel formation in a mouse model of lung cancer [26]. Notably, the explicit proangiogenic effect of RAAS could be additionally supported by tumor associated macrophages (TAMs), which express ACE and AT1R abundantly, and upon stimulation secrete further proinflammatory, proangiogenic, promigratory, prometastatic, and immunosuppressive agents, favoring cancer progression. Of note, the cardinal role of angiotensin receptor in this process was confirmed in a study with AT1R-deficient mice since in this setting fewer infiltrating macrophages were observed following cancer induction [10]. Furthermore, in prostate and pancreatic cancer, ANG II caused macrophage/monocyte chemoattractant protein-1 and 2 (MCP-1, MCP-2) and gonocyte colony-stimulating factor (G-CSF) release, leading to TAMs production and accumulation at tumor site. Clinically, this specific response is a well-known negative prognostic factor, especially in prostate cancer, corresponding with more aggressive tumor profile [27,28]. Finally, the contribution of RAAS to cancer-related inflammation is also evident and, as previously stated, closely related to RAAS-driven neoplastic angiogenesis and immunosuppression. In

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fact, local accumulation of ANG II, by inducing growth of cancer pathologic vasculature, triggers vascular leakage and hypoxic conditions, causing generation of reactive oxygen species (ROS) and oxidative stress (Fig. 1). The resulting protein modifications and cell damage lead to increase of AT1R, extending from neoplastic cells to their microenvironment, and the secretion of proinflammatory mediators, as indicated by a great number of reports reviewed elsewhere [29]. In the specific context of cancer, neoplastic cells with upregulated RAAS respond to ANG II by releasing: interleukin 8 (IL-8), transforming growth factor TGF-β and MCP-1, as well as by generation of ROS followed by the subsequent activation of hypoxia-inducible factor (HIF-1α) and NF-κB [30]. Moreover, fibroblasts, being the main source of cytokines in cancer milieu, upon ANG II stimulation produce TGF-β, IL-1α, IL-1β, IL-6, IL-8, MCP-1, M-CSF, cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). Immune cells, in turn, such as monocytes, were shown to release IL-1β when activated by ANG II, while TAMs overexpressing RAAS could release: MCP-1, IL-6, IL-8, TNF-α, GM-CSF, as well as adhesion molecules: P-, L-, E-selectin, intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), β2-integrin and α1-integrin [29,31]. Consequently, all these factors significantly exacerbate and sustain the inflammatory environment of cancer, favoring the disease progression and leading to cancer cachexia. Curiously, this terminal condition also belongs to the spectrum of processes regulated by RAAS, specifically on account of accumulation of TNF-α, IL-6 and ANG II. This effect significantly potentiates apoptosis of host cells and accelerates protein degradation through the ubiquitin-proteasome proteolytic pathway, as confirmed in a study with experimental rats [32].

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2.4. ACE-I in cancer treatment – clinical data

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The profound dysregulation of RAAS in malignancy together with its multi-directional contribution to the development and progression of neoplastic lesions, evidenced in preclinical studies, fully justify launching of clinical research towards its targeting in anticancer schemes. To date, however, the available clinical data seems insufficient as it primarily originates from re-analyses of clinical trials assessing various modes of antihypertensive therapies. Nonetheless, basing even on these limited information it can be presumed that ACE-Is are rather cancer-specific in terms of both, chemopreventive and therapeutic applications. For example, as evidenced by Lever et al. in the retrospective study conducted within the group of 5207 hypertensive patients, the decreased risk of incident 0.72 (95% CI 0.55-0.92) or fatal 0.65 (95% CI 0.44-0.93) cancers (especially female-specific and smoking-related) existed in a subgroup of 1559 individuals receiving enalapril, lisinopril or captopril for at least 3 years. These observations were not confirmed in patients receiving other antihypertensive agents, suggesting a specific, RAAS-related anticancer effect [33]. Furthermore, in a retrospective, case-control study by Lang et al. it was shown that ACE-Is reduced the occurrence of esophageal, pancreatic and colon cancer, secondary to the suppression of angiogenesis [34]. Also in a more recent study a decrease in the overall cancer risk in ACE-Is users among Taiwan population was reported [35]. These findings might actually translate into preferential use of ACE-Is in cardiology patients with additional indications for chemoprevention. As for their potential therapeutic use, it appears that the anti-RAAS agents provide the most benefis in adjuvant setting. For instance, the improved outcomes of patients undergoing classical platinum-based chemotherapy combined with ACE-Is was reported in the following malignancies: advanced non-small-cell lung cancer (NSCLC) (overall survival (OS) gain - 3 months) [36], advanced gastric cancer (OS gain - 5,7 months) [37] and metastatic CRC (OS gain - 11 months) [38]. To explain this effect, it should be noted that platinum-based chemotherapy was shown to induce VEGF secondary to AT1R upregulation as a mechanism of platinum resistance. Thus, the co-administration of ACE-Is or ARBs could serve as a way to increase cytotoxicity of these drugs, especially in long6

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term treatment [39]. The combination therapy with ACE-Is and anti-VEGF agents was also found to improve survival rates in subjects with metastatic RCC [40], metastatic CRC [38], glioblastoma [41] and advanced hepatocellular carcinoma (HCC) [38], probably by their additive antiangiogenic actions. In addition, the possible synergistic effect of ACE-Is and EGFR-targeted kinases, with the improved treatment results, was reported in NSCLC [42]. All these reports have been confirmed by the results of the most recent meta-analysis of survival outcomes by Li et al. in which, the potentiation of activity of chemotherapeutic agents used concomitantly with anti-RAAS drugs for multiple cancer types was suggested [43]. Finally, the clinical evidence on the advantageous effect of ACE-Is in the prevention of wasting syndrome in cancer patients was documented by a phase-III clinical trial, in which imidapril significantly reduced weight loss and muscle wasting in NSCLC and CRC but not in pancreatic cancer patients [44]. As suggested before, anti-RAAS treatment seems rather cancer-specific, meaning that some cancers for some reason could remain unresponsive to such intervention. Indeed, in the following malignancies: melanoma, multiple myeloma, acute myeloid leukemia, breast and female reproductive tract cancers ACE-Is did not show a positive result despite the fact that several of these cancers demonstrated abnormalities of RAAS expression [29]. There was also no assocacion between statins, ACE-Is or sartans use with the outcomes of patients with newly diagnosed glioblastoma treated with temozolomide and radiotherapy [45]. Furthermore, in a recent study by Ho et al., no prophylactic effect of ACE-Is and ARBs against HCC in patients with hepatitis B and hepatitis C virus infection was found [46], while in a population-based cohort study by Hicks et al, the increased risk of lung cancer in patients using ACE-Is was reported, especially in those treated for more than five years [47]. However, no explanation for the decreased efficiency of ACE-Is in all the above clinical settings was provided. Probably the minor role of RAAS itself in the development of these malignancies could be considered yet the source of this relationship still awaits its final clarification. Similarly, the reason for the insignificant role of ACE-Is and other antihypertensive agents in the chemoprevention of elderly hypertensive patients, as evidenced by Lindholm [48], remains unknown until now. In fact, in this study ACE-Is did not decrease new cancer occurrence in hypertensive elderly compared to other antihypertensive drugs, which stays in contrast with the results shown by Lang et al. and Lever et al. in general hypertensive population, discussed previously [33, 34]. This cardinal discrapency clearly needs verification in clinical trials. In conclusion, the conflicting nature of the results shown above stems from the fact that the majority of the available clinical data originate from non-representative, epidemiological observations within a non-heterogenous population of cardiology patients, or single-center clinical trials, which constitutes a major confounding factor. Therefore large, randomized, controlled clinical trials with long-term follow-up, evaluating the impact of ACE-Is on the development of cancer in the general population are necessary to conclusively assess their place in the cancer management. 2.5. ACE-Is in cancer treatment – mechanisms of action

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A significant number of pre-clinical results quite thoroughly explore pharmacodynamic aspects of ACE-Is-related mechanisms of anticancer action. In fact, available studies clearly indicate that ACE-Is, being pleiotropic drugs, can interfere with carcinogenesis in many areas, including: cell proliferation, apoptosis, migration, angiogenesis and muscle breakdown. Unexpectedly, in several reports also disadvantageous effects of ACE-Is were found, confirming multidirectional and contextdependent relationship between RAS-interfering agents and malignancy [3]. Effect on cell proliferation and apoptosis. The inhibition of cell proliferation in various cancer models was discovered primarily as an attribute of sulfhydryl-containing ACE-Is. In this respect, in experimental rats captopril decreased incidence and growth of radiation-induced cutaneous 7

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squamous cell carcinomas. It also retarded growth of chemically-induced syngeneic rat fibrosarcoma as well as decreased the number of mitoses in diethylnitrosamine-induced foci of pre-neoplastic cells in rat liver. In addition, captopril caused a reduction of tumor mass in various models of lung cancer secondary to its direct antiproliferatory and proapoptotic effect. Captopril was also shown to inhibit proliferation of human neuroblastoma, murine liver and lung carcinoma as well as hormone receptor positive and hormone receptor negative mammary carcinoma in a dose-dependent manner. Furthermore in leukaemic cell lines captopril and trandolapril inhibited cell growth, decreased c-myc expression and increased apoptosis, probably by increasing expression of TGF-β1 through Smad pathway. The antiprolifrative activity of ACE-Is in leukaemia could be also associated with decreaed degradation of AcSDKP which is a substrate to ACE and acts as an inhibitor of hemapoietic cells proliferation [49]. In contrast, there was no effect of captopril on tumor growth in human gliomas [3,50]. In addition to this, dicarboxylate-containing ACE-Is also exhibited antiproliferative and proapoptotic properties in cancer cells. For example, perindopril attenuated mitotic potential in hamster pancreatic duct carcinoma probably through modulation of proliferation-associated cell nuclear antigen (PCNA) and PKCβ growth-related genes. Moreover, enalaprilat reduced the growth rate of human neuroblastoma and significantly attenuated invasiveness of gastric cancer [3,51]. In leukaemia, in turn, the mechanism of enalapril-induced apoptosis could involve modulation of STATA5 gene associated with JAK-STAT pathway [52]. Finally, trandolapril decreased cell growth, lowered c-myc expression and stimulated apoptosis in leukemic cells [53]. Effect on cell migration. Captopril, perindopril and enalaprilat have been shown to inhibit the bFGF-induced capillary endothelial cell migration in a mechanism unrelated to ANG II [3]. For this reason currently the antimigratory properties of ACE-Is are mainly associated with their suppression of MMPs, the proteolytic enzymes with the zinc-containing active site that share a structural homology with ACE. MMPs are responsible for degradation of the extracellular matrix (ECM), which facilitates cell migration and serves as an important step of malignant cell extravasation that paves the way through the peripheral tissue for invasion and metastatic spread. MMPs are also be involved in the formation of metastatic niche.Thus inhibition of MMPs could potentially suppress the invasive potential of tumors [3,14]. Given structural similarities between ACE and MMPs, ACE-Is are known to exhibit the affinity to MMPs zinc-containing active site (especially in MMP-2 and MMP-9). They inhibit it competitively through zinc-chelating mechanism, as evidenced for captopril in Lewis lung carcinoma, human glioma and human gastric xenograft [3,54–56]. Furthermore, the inhibitory activity against MMPs was confirmed for lisinopril, quinapril, imidapril and enalapril yet in studies investigating the process of left ventricular remodeling [57,58]. In addition, the most recent report indicates that the antagonism with ANG II could also account for reduced migratory potential of melanoma cells by reversing decreased focal adhesion, as evidenced by Alvarenga et al. [59]. Effect on angiogenesis. Impairment of angiogenesis deprives tumor of nutrition and oxygen necessary for local growth and metastasis, ultimately leading to retardation of its development. The inhibition of cancer angiogenesis was reported for both, sulfhydryl-containing and dicarboxylatecontaining ACE-Is, predominantly through suppression of VEGF. Specifically, this was confirmed for perindopril in a murine HCC model as well as in head and neck squamous cell carcinoma [2]. In HCC model, however, the antiangiogenic effect of perindopril was more potent in a combination with other agents. For example when combined with 5-fluorouracil it reduced hepatoarcinogenesis significantly, while individually both of these drugs inhibited tumor growth via VEGF attenuation only minimally [60]. The combination of perindopril plus interferon-β as well as perindopril plus vitamin K also inhibited HCC growth synergistically via reduced angiogenesis. Interestingly, a more potent antiangiogenic activity of single perindopril was shown in these studies when compared with single interferon-β or single vtamin K [61,62]. Perindopril also inhibited in vitro endothelial cell tubule formation in BNL-HCC cells [3]. Besides, captopril, which is a sulfhydryl donor, exhibited a dualistic

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2.6. ARBs in cancer treatment – preclinical data

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antiangiogenic effect, involving facilitation of angiostatin production and abolition of MMPs,which results in reduced capillary endothelial cell migration and decreased neovascularization [54]. Physiologically, angiostatin is a potent endogenous inhibitor of angiogenesis while its formation requires plasminogen, plasmin and sulfhydryl residue. In preclinical setting, the co-administration of captopril with tissue plasminogen activator in human melanoma xenograft model resulted in a 83% decrease in tumor volume secondary to reduced angiogenesis. This effect was more significant than that of captopril alone, clearly suggesting the angiostatin-dependent response [63]. Effect on TAMs recruitment. The anticancer activity of ACE-Is also involves their attenuation of TAMs infiltration. In one available study, treating lung adenocarcinoma-bearing mice with enalapril prevented the amplification of cancer-induced self-renewing hematopoietic stem cells (HSCs) and macrophage progenitor by reestablishment of expression of sphingosine-1-phosphate receptor 1 (S1P1) in HSCs. Thus, the proliferation of TAMs progenitors in the spleen was inhibited and their accumulation in lungs decreased, which in turn reduced cancer growth and improved animal survival [64]. Effect on muscle atrophy. Finally, the reduction of proteolytic muscle breakdown in cancer cachexia also seems to support the concept of ACE-Is repurposing in oncology. In particular, imidapril significantly reduced ANG II-mediated degradation of proteins in murine myotubes [3], whereas perindopril administered to cachectic mice bearing colon tumors reduced cancer growth, improved locomotor activity and decreased fatigue of tibialis anterior muscles in situ, yet it did not enhance body or muscle mass [65].

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As with ACE-Is, there is a theoretical rationale behind the use of ARB in cancer management, explained by AT1R overexpression in certain cancer types corresponding with disease progression. Several experimental studies confirmed the applicability of this strategy. For instance, the administration of candesartan to a mouse renal-cancer-lung-metastasis model caused a reduction of the number and volume of lung lesions, accompanied by inhibition of tumor-associated angiogenesis and VEGF expression [66]. Candesartan also inhibited growth and neovascularization of sarcoma cells, fibrosarcoma cells and diminished metastatic lung burden of Lewis lung carcinoma cells [67]. Additionally, tumor-induced overexpression of VEGF was decreased by candesartan, losartan and valsartan in gastric cancer xenografts, human prostate cancer xenografts, murine pancreatic tumor model and mouse melanoma syngeneic tumors. Antiangiogenic properties of irbesartan, resulting in suppression of tumor growth and decrease in a number of liver metastases, were also confirmed in a study involving a mouse model of CRC liver metastases [2]. The same mechanism was responsible for suppressing pancreatic cancer development after combined gemcitabine and losartan treatment in a murine model. Interestingly, both drugs gemcitabine and losartan, when used alone exerted only a moderate anti-angiogenic effect [68]. Olmesartan, in turn, caused the significant reduction of the invasiveness of gastric cancer cell lines N87 and MKN45, yet it also stimulated their proliferation [3]. In addition, telmisartan inhibited tumor growth in CCA xenograft model via inducing G0/G1 cell cycle arrest [69]. Finally, ARBs have been shown to exert immunomodulatory actions. In prostate cancer, they reduced TAMs infiltration and inhibited MCP-1 expression via attenuating PI3K/Akt signaling [27]. Also in pancreatic cancer ARBs diminished the synthesis of MCP-1 through downregulation of ERK1/2 and reduced activity of NF-κB [28]. In a mouse model of melanoma, in turn, they decreased TAMs infiltration and their VEGF secretion, thus reducing angiogenesis [70]. Finally, in a most recent study losartan improved paclitaxel delivery to ovarian cancer model by reducing extracellular matrix content (anti-fibrotic action) and the associated solid stress. These experimental observations were further confirmed in a retrospective analysis of ovarian cancer patients survival. In fact, although 9

losartan alone did not impact tumor burden it significantly enhanced paclitaxel cytotoxicity [71]. Unfortunately, the available experimental results on ARBs anticancer activity are inconsistent across the published studies since in several cases, discussed in our previous report, the blockade of AT1R caused stimulation of angiogenesis [3]. Therefore drug-specific properties and cancer genetic background must be evaluated prior to the final establishment of ARBs’ role in oncology. 2.7. ARB in cancer treatment – clinical data

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In the light of the above preclinical data, the clinical findings on the impact of ARBs on cancer incidence are quite surprising. Unexpectedly, a number of human trials and meta-analyses indicated that there was an increased risk of newly diagnosed cancers among ARBs users. This issue was first raised in 2003 by CHARM-Overall study [72] and was confirmed by further investigations, as depicted in Table 1.

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In this context, however, it should be noted that the increased risk of malignancy demonstrated by individual trials (ONTARGET, PROFESS) was frequently insignificant. One reason for this could be an insufficient number of identified cases and a relatively short follow-up – not covering the time needed for cancer to develop. Another confounder may be the fact that all the clinical trials in question concerned primarily cardiovascular endpoints and only in three of them the development of cancer was a pre-defined endpoint (LIFE, ONTARGET, and TRANSCEND). Nonetheless, in LIFE and TRANSCENDENT the risk of malignancy was significantly higher in ARBs group than in controls. Eventually, these clinical observations were debated by FDA in 2011, and the official position of the agency ultimately declined the link between ARBs use and malignancy incidence, emphasizing that patient cardiovascular benefit outweighs the potential risk [85]. This, however, indicates that the use of ARBs, unlike ACE-Is, in cancer prophylaxis is not justified. Notwithstanding, more recent investigations evaluating ARBs applicability in adjuvant setting provided some optimistic results. For instance, an interim analysis of II phase trial indicated that there was an encouragingly high microscopically margin-negative resection rate in patients suffering from locally advanced pancreatic cancer receiving neoadjuvant losartan plus FOLFIRINOX chemotherapy [86]. Prolongation of OS and progression free survival (PFS) in patients with metastatic CRC receiving a combination of ARBs and bevacizumab was also reported [38]. Similarly, there was a positive effect of the reduced tumor marker level, decreased proliferation and apoptosis, and retarded muscle breakdown in patients with gastric cancer receiving telmisartan with 5-fluorouracil [87]. Finally, candesartan with androgen ablation caused PSA stabilization and improved performance status in patients with hormone-refractory prostate cancer [88]. Taken together, these data clearly indicate that the impact of ARBs use on cancer is highly context-dependent yet the combination with standard chemotherapy seems to offere more benefits than monotherapy.

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3. SNS and beta blockers SNS is another human key regulatory mechanism whose function can be impaired by neoplastic signalling, providing thereby an additional target for anticancer interventions. Physiologically, SNS operates continuously to modulate the vital functions of most organs. The motor pathway of SNS consists of a cholinergic, preganglionic neuron and an adrenergic, postganglionic neuron releasing norepinephrine (NE) into target visceral tissues. The activation of SNS also stimulates the release of epinephrine (EPI) from the adrenal glands into the bloodstream, which potentiates the sympathetic effects. Catecholamines (NE and EPI) exert their actions through two major subtypes of adrenoreceptors, i.e.: alpha (α1, and α2) and beta (β1, β2 and β3), that are widely 10

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expressed in most mammalian tissues, yet they display heterogenous distribution and different downstream signalling pathways [4]. SNS’s primary function is to induce rapid fight-or-flight responses to physiological or environmental threats. It also regulates acute (physiological or emotional) and chronic stress, currently considered as the major risk factor for carcinogenesis, resulting from the accumulation of catecholamines. This relationship has been already sufficiently confirmed in numerous in vivo studies for ovarian, prostate, pancreatic and breast cancer. Indeed, local concentration of NA in ovarian carcinoma was shown to be substantially higher in patients affected by mental stress, which was identified as a negative prognostic factor for disease progression [89]. What is more, perioperative stress with the consequent excessive concentration of catecholamines was shown to both, predispose to cancer initiation in patients without cancer history and to cause cancer progression in the malignancy-affected population [90]. Particularly, the tumour-promoting effects of social stress were linked to overstimulation of β2 and β3 adrenoreceptors (BARs) inducing downstream cAMP signalling [91], as evidenced by pharmacologic analyses of ovarian, breast and prostate cancer models. At the molecular level, the principal messenger implicated in the BARs-mediated procarcinogenic effects is protein kinase A (PKA), since it regulates a variety of cellular responses related to: metabolism, growth, differentiation, death or gene transcription, etc. Therefore, BARs blockers (BBs), drugs originally developed for the treatment of cardiovascular diseases, might provide new therapeutic opportunities for the control of stress-driven cancers [4].

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3.1. Malignancy-induced structural alternations in SNS

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The contribution of SNS to malignancy lies mostly in its excessive stimulation occurring in both, neoplastic cells and various elements of their microenvironment, i.e.: epithelial cells, vascular myocytes, pericytes, adipocytes, fibroblasts, neural cells, glial cells, lymphoid and myeloid immune cells. Its structural malformations, induced by cancer pathologic signalling, are therefore largely intended either to provide a source of catecholamines or to extend their access to appropriate responsive elements. Consequently, the marked overexpression of BARs is a common occurrence in the variety of cancer contexts, particularly in brain, lung, liver, stomach, colon, kidney, adrenal glands, breast, ovary, prostate, lymphoid tissues, bone marrow, skin and vasculature [4,6]. In addition to this, the increased density of BARs can further correlate with lymph node metastasis, tumour size and its clinical stage, as evidenced in oral squamous-cell carcinomas [4]. Alternatively, cancer can exploit SNS by the autonomous expression of catecholamine-synthesizing enzymes, providing an independent supply of catecholamines to facilitate progression [92,93]. To amplify this effect, some tumour cells can acquire the additional ability to secrete axon guidance molecules and neurotrophic factors, including brain-derived growth factor and nerve growth factor, that stimulate formation of novel nerve endings. Indeed, there is experimental and clinical evidence showing that pancreatic, prostate, oesophageal and cardiac carcinomas are innervated by pathologic nerve fibres forming with tumour mass functional neuro-neoplastic synapses that secrete local neurotransmitters, including catecholamines. Furthermore, histologic analyses of the human breast and ovarian cancer innervation pattern demonstrated extensive perivascular innervation and occasional radiation of nerve fibres into tumour parenchyma, which could provide NE supply to modulate responses of BARs. Some experimental data also indicate that locally-available EPI or NE, unlike systemic ones, serve as the predominant source of protumorigenic catecholamines. In fact, in ovarian cancer, a significantly higher concentration of NE in tumour mass was found when compared to circulating blood. Concomitantly, no EPI was detected intratumorally. Also the local level of NE, but not the blood

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levels, correlated with tumour gene expression profiles and patient psychological risk factors [4,92,94]. 3.2. The contribution of SNS to carcinogenesis

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The physiological consequences of cancer-driven local malfunction of SNS have been studied as a follow-up to the establishment of an epidemiologic link between behavioural stress and progression of incident malignancies. Additional stimulus to that kind of research were accumulating clinical observations suggesting that the use of BBs could reduce the risk of progressive disease. Numerous experimental studies performed so far have uncovered the sophisticated and pleiotropic function of BARs in the regulation of processes underlying cancer development, including: apoptosis, proliferation, growth, migration, cell adhesion, MMP-associated invasion, angiogenesis, inflammation related to IL-6 and IL-8 release, epithelial-mesenchymal transition and metastasis, as shown on Fig. 2 [89]. These observations have clearly demonstrated that SNS, similarly to RAAS, plays a pivotal role in regulating protumorigenic effects, making BBs an interesting option for repurposing program. Proliferation and apoptosis. A number of available reports support the concept of substantial growth- and survival-promoting actions of EPI and NE in neoplastic cells, particularly in pancreatic, breast, ovarian, CRC, lung, prostate, oesophageal cancer, melanoma and leukaemia [92,95]. For instance, it has been shown that EPI influences growth of nitrosamine-induced tumors in hamster lungs [96]. Also the non-selective β-adrenergic agonist - isoproterenol stimulated the synthesis of DNA in human NSCLC cells [97]. Furthermore, in the mouse model of ovarian cancer, elevated NE level correlated with tumour aggressiveness and growth. Similar effects were observed after stimulation of ovarian cancer cells by terbutaline – potent β2 agonist. Propranolol, however, reversed these actions owing to its nonselective BAR-antagonistic properties. Analogously, in CRC and gastric cancer cells stimulation of B2AR caused an increase in cell proliferation [89,92]. Molecularly, this effect could have been associated with stimulation of MAPK/ERK and p43/p44 signalling, as evidenced in pancreatic cancer cells and melanoma [98,99]. The BAR-dependent cancer proliferation could also involve PKA/BARK (β adrenergic receptor kinse)/β-arrestin/Src/Ras/MAPK pathway [92] or transactivation of EGFR, as shown in NSCLC cells [92]. Consistently with the above assumptions, in CRC cells B2AR inhibitors suppressed tumour growth via trans-inactivating EFGR-Akt/ERK1/2 signalling [100]. Besides, one animal study found that ovarian cancer cells activated by NE or EPI exhibited a lower level of anoikis, which is a mode of apoptosis induced after the loss of cell adhesion to ECM. The pathway responsible for this effect was identified as B2AR-related, G-proteinindependent mechanism involving actin/Src/focal adhesion kinase (FAKy397) [101]. Furthermore, in prostate and breast cancer, overstimulation of BARs by EPI diminished the apoptotic potential of cells via BAR/PKA-mediated BAD downregulation [92]. Finally, treatment of breast adenocarcinoma cells with stress hormones in in vitro setting reversed the G2/M cell cycle arrest and decreased the cytotoxicity of paclitaxel, indicating that catecholamines can induce resistance to standard chemotherapy [96]. In a similar way, a selective B2AR blocker ICI 118,551 enhanced the antiproliferative and proapoptotic effects of gemcitabine in pancreatic cancer cells via the mechanism involving inhibition of gemcitabine-induced NF-κB expression, together with down-regulating BCL-2 and increasing proapoptotic BAX [102]. Furthermore, propranolol sensitized HER2 positive breast cancer cells to trastuzumab [103]. Migration, invasion, adhesion and metastasis. Despite the confirmed effect of BARs on proliferation and apoptosis, the contribution of SNS to carcinogenesis seems to be associated mainly with tumour progression, not its promotion. Thus, the growth-stimulating effects of SNS appear to be less significant than its promigratory and prometastatic actions. In other words, the responsiveness to EPI/NE stimulation, resulting from BARs overexpression, is thought to increase the malignant

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phenotype of cancer cells in the first place, while the stimulation of growth of the primary tumour, if occurs, probably plays the secondary role. This specific relationship was confirmed in a study with a mouse model of breast cancer, in which chronic stress only minimally affected the growth of the primary tumour, yet it significantly increased metastases to distant tissues. The observed actions correlated with intensive B2AR activity, infiltration of macrophages into the primary tumour and a prometastatic gene expression signature, and they were reversed by β-antagonist, propranolol [104]. Another probable prometastatic pathway associated with BARs could probably be linked with RANKL overexpression in bone marrow osteoblasts, which determined the increased migratory potential of neoplastic cells, as evidenced in a mouse model of metastatic breast cancer [105]. The increased metastasis to lumbar lymph nodes was also reported in the mouse model of prostate cancer [96]. Of interest, in many solid epithelial cancers, prometastatic effects of BAR stimulation relied on PKA downstream signalling [106]. Furthermore, multiple animal and in vitro experiments indicated that stress hormones potentiated the activity of MMP-2, MMP-7 and MMP-9. This mechanism was particularly responsible for increased motility of primary and metastatic melanoma [98]. Additionally, NE was shown to facilitate adhesion of breast cancer cells to the human pulmonary microvascular endothelium by β1-integrin and growth-regulated oncogene α signalling, the effect corresponding to the process of neoplastic extravasation. Finally, catecholamines were shown to exert chemokinetic and chemotactic actions in studies with colon, prostate, ovary and breast carcinoma cell lines [107]. This implies that the concentration of EPI and NE could determine the direction of cancer cell migration, being responsible for their increased migratory potential. Curiously, there are suggestions that organs producing NE, such as: adrenal glands and brain can become common sites of metastases for several cancers on account of the ability of catecholamines to recruit tumour cells [96]. Angiogenesis. Another intriguing aspect of β-adrenergic influence on tumour progression is promotion of angiogenesis, as evidenced in multiple myeloma, melanoma, ovarian, nasopharyngeal [96], pancreatic and colon cancer [106]. In this context, catecholamines were suggested to induce expression of VEGF in neoplastic cells. They could also stimulate MMP-9 in both, neoplastic cells and TAMs, promoting thereby formation of tumour pathologic vasculature, which was confirmed in ovarian carcinoma [92,108]. Other proangiogenic molecules released in response to BARs stimulation include: IL-6, IL-8, MMP-2, MMP-9 and HIF-1α, and they were recognized in: prostate, breast and liver cancer cells. Of interest, the administration of propranolol abolished proangiogenic responses stimulated by catecholamines and this effect was repeatedly reported in the above-referred publications [92]. Immunosuppression. Several epidemiological data suggested that surgical stress could facilitate the growth of pre-existing micrometastases and small residual tumours postoperatively. One probable mechanism behind this effect may involve local and systemic release of catecholamines that mediate postoperative immunosuppression. In fact, studies have shown that catecholamines suppressed the cytotoxicity of natural killers (NK) and T helper type 1 cytokines, compromising the resistance to metastasis after surgery [109]. Other mechanisms responsible for this effect were, however, not excluded and thus, the exact molecular process responsible for the postsurgical tumour growth still remains uncovered. Other mechanisms. Available scientific reports also suggest several alternative pathways of the SNS-mediated cancer progression. They include inhibition of p53-dependent DNA repair, inhibition of type I IFNs, upregulation of HER-2 pathway, induction of epithelial-mesenchymal transition [4] and induction of COX-2 expression [106], yet their relevance is less well-established in the literature and thus, their discussion was omitted in this review. 3.3. BBs in cancer management – clinical data

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As numerous pieces of preclinical evidence support the concept of a meaningful contribution of BARs to tumour progression, the use of BBs in cancer patients appeared as an appealing adjuvant strategy with pleiotropic effect affecting all: primary lesions, their microenvironment and secondary metastatic tumours. In fact, several clinical data confirmed this hypothesis, especially in the following cancer types: melanoma, breast, ovarian, lung and prostate, reviewed in detail by Tang et al. and Ishida et al (Table 2) [92,110].

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What is more, in breast cancer patients treated with trastuzumab and propranolol, the improved PFS and OS rates were reported when compared to trastuzumab alone, suggesting the efficiency of BBs in overcoming HER2 resistance. This activity was particularly explained by the activation of B2AR-mediated trastuzumab resistance-dependent PI3K/Akt/mTOR pathway, successfully abolished by propranolol [103]. In addition, two meta-analyses: by Choi et al. and Weberpals et al. confirmed the beneficial effect of BBs in malignancy, manifested by the improved survival of patients with early-stage disease [125], as well as in patients with breast cancer using BBs in post-diagnostic setting [126]. By contrast, other studies yielded antagonistic results, emphasizing no survival gain associated with BBs administration, especially in the following cancers: breast, prostate, lung, stomach and renal [92,110,118]. Also, two recent meta-analyses denied the link between BBs and cancer survival. In detail, in the report from 2018 by Zhijing et al., involving thirty-six casecontrol and cohort studies with 319,006 patients, BBs had no impact on the general cancer prognosis either in early (I/II) or in advanced (III/IV) disease stage. A subgroup analysis, in turn, implied that BBs were positively correlated with patient prognosis in melanoma, breast and pancreatic cancer, while no association was found in lung, ovarian, CRC and mixed cancer [127]. In addition, in the metanalysis of twenty-seven studies from 2018 by Yap et al. the use of BBs was not correlated with general cancer recurrence. In subgroups, however, the disease-free survival (DFS) and OS were prolonged in melanoma and ovarian cancer, while in endometrial and head and neck, prostate and lung cancer DFS and OS were reduced [128]. Currently, the results of clinical trials evaluating the prophylactic, anti-immunosuppressive efficiency of BBs in breast cancer (NCT00502684) and CRC (NCT00888797) in peri-operative setting are being anticipated. In summary, the inconsistence of the results obtained from the nonrandomized, observational trials clearly indicate that further similar protocols are unlikely to ultimately determine the place of BBs in current oncology. As with ACE-Is, the limitations of epidemiological research and the inherent biases clearly justify the need for randomized controlled trials assessing the potential protective effect of BBs, primarily on cancer progression and metastasis. The issues that seem to require the most urgent examination are: 1) the superiority of non-selective BBs that modulate β2 receptors (propranolol) over cardio-selective β1-antagonists (atenolol); 2) the selection of appropriate dosing regimen; 3) the selection of appropriate type and stage of malignancy; 4) the utility of blood-brain barrier crossing propranolol in the inhibition of BAR expressed in the central nervous system.

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3.4. The mechanism of BBs-related anticancer action The discussed epidemiological studies and the earlier experiments on the correlation between stress and cancer have already shed some light on the potential mechanism of anticancer action of BBs. In fact, it is currently believed that their pleiotropic activity includes: inhibition of proliferation, activation of apoptotic pathways, inhibition of angiogenesis and the most notably – inhibition of migration and invasion. These actions are, in turn, associated mainly with the attenuation of B2AR and the resulting inhibition of the downstream PKA signalling, with reduced VEGF and MMPs in various solid and hematological malignancies. Thus, the most prominent role of BBs can be defined as being

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related to the modulation of cancer metastasis/recurrence rather than to its primary development. Table 3 demonstrates the outline of the preclinical data on BBs anticancer performance.

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In this context it is also worth to emphasize that the anti-proliferative and anti-angiogenic activity of BBs varies across the known agents and using this criterion they can be divided intro three subcategories: potent (i.e., carvedilol and nebivolol), intermediate (i.e., propranolol and labetalol) and weak (i.e., atenolol, metoprolol and butoxamine), as evidenced in neuroblastoma cells [156]. Furthermore, based on the available preclinical analyses, it can be stated that their anti-tumor effect seems insufficient for monotherapy, however they exhibit a fine potential for serving as adjuvants since they significantly potentiated the effect of concomitant chemotherapeutic agents. In fact, the inapplicability of porpranolol for monotherapy was confirmed e.g. in triple-negative breast cancer as its cytotoxicity (IC50 30 mg/ml) was much lower than that of doxorubicin (IC50 0.01 mg/ml) and 5fluorouracil (IC50 6 mg/ml) [157]. However, its anti-proliferative effect was revealed to be weaker (observed only in supra-therapeutic concentrations) than its anti-angiogenic activity (significant in low concentrations). This curious relationship was evidenced in bresst, NSCLS, neuroblastoma and glioblastoma cell lines. In addition to this, propranolol, unlike microtubule-depolymerizing agents had almost no vascular-disrupting activity. Furthermore, in triple-negative breast cancer low concentrations of propranolol combined with paclitaxel and 5-fluorouracil showed a significant potentiation of cytotoxic and anti-angiogenic response [158]. Besides, the survival of neuroblastomabearing mice was significantly increased for the combination of carvedilol or propranolol with vingristine (29 and 30 days, respectively). For comparison, the survival of the study animals for single agents was 5 days for propranolol, 4 days for carvedilol and 7 days for vincristibe. The antiproliferative efficiency of microtubule-targeting agents (vinblastine, vincristine and paclitaxel) against neuroblastoma cells in vitro was also increased by carvedilol and propranolol, but not by nebivolol. BBs, however, did not affect the activity of doxorubicin, etoposide, carboplatin and melphalan in this model [156]. Based on these findings, it seems plausible that BBs are the most potent in multi-drug schemes, which represents a good rationale for clinical trials launching. To conclude, in the context of BBs repurposing, although the available clinical results are conflicting, the amount of evidence supporting this hypothesis is still large enough, that further investigations in this area are justified and advisable. In fact, the greatest therapeutic advantage of BBs use could be achieved in patients with early-stage cancer treated primarily with surgery, early-stage melanoma, breast and prostate cancer, as their main antineoplastic action focuses rather on inhibiting the micrometastatic spread than on chemoprevention or treatment of advanced tumours. Propranolol, as non-selective, blood-barrier crossing beta antagonist, seems to be preferred, probably in adjuvant or neoadjuvant setting, for example in cases with increased anxiety levels. Furthermore, BBs could be used for the enhancement of standard chemotherapy effectiveness by overcoming tumour resistance to paclitaxel, gemcitabine or trastuzumab. The applicability of BBs as adjuvants to chemotherapy would, however, need a thorough examination in clinical setting.

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4. Statins

The fourth group of the cardiovascular system-related drugs, possibly implicated in the modulation of anticancer response, are statins, i.e.: the competitive inhibitors of 3-hydroxy-3methylglutarl coenzyme A (HMG-CoA) reductase, initially associated with reducing hypercholesterolemia. In cardiology, they are indicated in the primary and secondary prevention of coronary heart disease for exhibiting a wide spectrum of benefits, originating not only from their principal lipid-lowering actions, but also from the alternative pharmacological activities, such as: prevention of platelet aggregation, inhibition of inflammation, decrease of oxidative stress, inhibition 15

of cell proliferation, modulation of angiogenesis, etc. The putative mechanism behind these pleiotropic effects is the abolishment of isoprenoid intermediates and this molecular pathway, at least partially, sets the connection between statins and cancer [159]. 4.1. Molecular target of statins

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Statins interfere with the second step of cholesterol biosynthesis and thereby they prevent mevalonate formation from HMG-CoA, as shown in Fig. 3. Mevalonic acid, in turn, aside from being a precursor of cholesterol, also participates in the biosynthesis of farnesyl pyrophosphate (FPP) and geranyl-geranyl phosphate (GGPP) – both required for posttranslational modification of ubiquinone and small G-proteins, including: Ras, Rac, Rab and Rho. Physiologically, attaching FPP or GGPP residue to G proteins enhances their ability to anchor in membranes and thus, it is considered as a crucial step for their full activation. Consequently to decreasing isoprenylation of essential signalling proteins, statins indirectly disrupt their coupled transduction pathways that regulate growth, proliferation, migration, cytoskeleton function and death [160]. Of interest, this effect occurs at the conventionally-used doses, recommended for the treatment of hypercholesterolemia [161], indicating that the potential use of statins in cancer management could be convenient and well-tolerated by patients.

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Early toxicological, in vitro and animal studies initially supported the hypothesis that statins might be associated with the development of neoplastic conditions [162]. Similarly, several cardiovascular system-related clinical trials suggested that they could be responsible for increased mortality [160], especially in breast (1,5 fold increase) and prostate cancer (1,2 fold increase) [163– 165]. In line with this, a meta-analysis of randomised clinical trials of cholesterol reduction found a slight but statistically insignificant increase in cancer death among the statin-treated population [166]. Although these findings were interpreted as coincidental, they increased the interest in epidemiological research assessing the connection between statins and cancer risk. Accordingly, subsequent cardiovascular clinical trials encompassed cancer incidence as a secondary endpoint. Larger metanalyses, however, abolished this concept [160,167] and strikingly, provided a number of results to support the counter-hypothesis that statins might actually exert chemopreventive actions, specifically against the following malignancies: melanoma, breast, colon, uterine and prostate, as detailed in Table 4 [168].

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In fact, their prophylactic effects were the most remarkable in CRC patients, also in the highrisk ones, such as those with a family history of colorectal malignancy, inflammatory bowel disease and hypercholesterolemia. In addition, three meta-analyses suggested protective efficiency of statins against breast cancer reoccurrence, manifested by reduced rate of disease relapse among users versus non-users, improved OS, cancer-specific survival and reduced all-cause mortality rate [175–178]. Consistently, in a recent systematic review and meta-analysis of observational studies by Zhong et al. the benefits of pre- and postdiagnostic use of statins were seen in CRC, prostate and breast cancer patients [178]. Of interest, the advantageous effects of statins were probably unrelated to their cholesterol-lowering actions, as fibrates failed to provide cancer protection [170]. Graaf et al., in turn, reported that statin-dependent chemoprevention remained clinically relevant only for long-term use exceeding 4 years, or if more than 1350 defined daily doses were taken [174]. By contrast, no association between cancer risk and statins was reported in bladder, breast, endometrial, kidney, lung, pancreatic, skin and mixed malignancies [168]. Moreover, a secondary analysis of two large clinical 16

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trials provided no proofs for the correlation between statins and the survival in patients with newly diagnosed glioblastoma [45]. Besides their chemopreventive potential, several reports also indicated that statins could exhibit therapeutic actions. For example, in a phase I/II trial, a modest anticancer response of highdose lovastatin with an excellent safety profile was reported in patients with anaplastic astrocytoma and glioblastoma multiforme [179]. Furthermore, a survival over 22 months of two paediatric patients with anaplastic astrocytoma of initially poor prognosis treated with fluvastatin 8 mg/kg/day was described [180]. The promising results are also available for statins in adjuvant treatment of HCC. In fact, in a randomized, controlled trial, patients with advanced HCC administered with pravastatin at a dose of 40 mg daily (after transcatheter arterial embolization followed by oral 5-fluorouracil 200 mg daily for 2 months) had a longer median survival rate (18 months) than those in placebo group (9 months) [181]. Also combined treatment of chemoembolization and pravastatin improved survival of patients with advanced HCC in comparison to chemoembolization alone [182]. Similarly in a study which compared pravastatin 40 – 80 mg daily for 5 months with gemcitabine 80-90 mg/m2 weekly every 4 weeks or octreotide 3 x 200 µg/day for 2 months followed by 20 µg octreotide LAR every 4 weeks in advanced HCC, the pravastatin group reached the longest median survival rate of 7,2 months when compared to 5 months in the octreotide group and 3,5 months in gemcitabine group [183]. [184]. The efficiency of idarubicin, cytarabine and pravastatin scheme in acute myeloid leukaemia was also confirmed [185]. Finally, the advantageous activity of statins in breast cancer patients was suggested, since the increase of their intracellular HMG-CoA reductase correlated with the maintenance of less aggressive tumour phenotype and prolonged DFS [186]. In prostate cancer, in turn, the potential radiosensitising effect of statins was observed [187]. On the contrary, the combination of pravastatin with standard chemotherapy had no impact on the treatment outcomes in lung cancer, as evidenced in a randomized, phase III study involving 846 patients [188]. Aside from this, also several experimental studies provided additional data to support the use of statins in adjuvant treatment. For example, lovastatin potentiated proapoptotic effect of 5-fluorouracil and cisplatin in various colon cancer cell lines, although the effect of single lovastatin was minor. In this study adding lovastatin to chemotherapy was also more effective than monotherapy with increasing concentrations of cisplatin [189]. Lovastatin also augmented the antitumor activity of cisplatin in both in vitro and in vivo murine melanoma model [190], as well as in human leukaemia K562 and HL-60 cell lines the synergistic anticancer effect of paclitaxel and lovastatin was shown [191]. Of note, in the letter sudy lovastatin alone was less cytotoxic than paclitaxel alone. Additionally, lovastatin increased the antineoplastic efficiency of doxorubicin, with concomitant reduction of its cardiotoxicity, which was evidenced in a murine model of melanoma, colon and lung carcinoma [192] Again, in this experiment the effect of combination treatment was more pronounced than that of either drug alone, however doxorubicin was more cytotoxic than lovastatin individully. The combined therapy of lovastatin and tumour necrosis factor (TNF-α) also resulted in reduced tumour growth and prolonged survival of melanoma-bearing mice [193]. Finally, addition of fluvastatin, simvastatin and atorvastatin to paclitaxel or topotecan-based chemotherapy caused enhanced inhibition of cell growth and cytotoxicity, compared to either agent alone in aggressive NK cell leukemia in vitro [194]. Eventually, there are also suggestions that specific modifications of statins’ pharmaceutical form, by incorporating them in nanoparticulate drug delivery systems, could enhance their antineoplastic performance. For example, pravastatin encapsulated in long circulating liposomes decreased murine melanoma tumour growth by 70% more effectively than free pravastatin [195]. Also, pravastatin loaded chitosan nanoparticles exhibited improved cytotoxicity when compared to single pravastatin in HCC model [196]. These novel formulations, however, still await their examination in clinical trials.

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4.3. Anticancer effect of statins in experimental studies – mechanism of action

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Available pre-clinical studies explain to some extent the mechanism of statins’ anticancer activity. As outlined above, their interference with posttranslational isoprenylation of G-proteins leading to their dysfunction probably destabilizes the signaling pathways that modulate apoptosis, proliferation, differentiation, angiogenesis and proteasome (Fig. 3). Apoptosis. Statins were shown to induce apoptosis in numerous neoplastic cell lines of both, solid and hematologic malignancies. For instance, lovastatin reduced the survival of astrocytoma, squamous cell carcinoma of the cervix and head and neck, monomyelocytic leukemia, rhabdomyosarcoma, medulloblastoma [160], neuroblastoma, and acute myeloid leukaemia, with the latter two being the most susceptible [197]. Furthermore, in another study it was found that cerivastatin was 10 times more potent than lovastatin, fluvastatin and atorvastatin in triggering tumour-specific apoptosis of acute myeloid leukaemia cells [198]. At the molecular level, these effects involved upregulation of proapoptotic BAX and Bim, downregulation of antiapoptotic BCL-2, and activation of caspases, with cerivastatin increasing caspase-3, -8 and -9 in human myeloma cells and lovastatin increasing caspase-3 and caspase-7 in prostatic epithelium and leukaemia cells, respectively. Curiously, the statin-induced apoptosis was reversible by immediate products of HMG-CoA reductase, namely mevalonate and GGPP, but not FPP. This effect indicates that geranylgeranylation of Rho, Rac and Rab families is an essential downstream component of the mevalonate pathway for statin-induced apoptosis, specifically in acute myeloid leukaemia and colon cancer. Ras, in turn, seems to play a secondary role, as under physiological conditions it usually undergoes farnesylation, which failed to oppose the proapoptotic actions of statins [189,198]. Cell growth. Interference with translocation of Ras and Rho to the cell membrane, required for proproliferative and promigratory signal transduction, suggests that statins might hinder malignant cell growth. Indeed, in the study by Denoyelle et al. cerivastatin repressed cell proliferation and invasion of aggressive breast cancer cell line, and this effect was attributed to G1/S cell cycle arrest caused by upregulation of p21. The described cellular response was probably RhoA-dependent since the counterregulatory actions were observed after the addition of GGPP, but not by FPP [199]. Similarly, fluvastatin reduced the growth of RCC lines by inducing cell cycle arrest at the G1 phase, accompanied by activation of cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p53 [200]. Lovastatin, in turn, inhibited the growth of pancreatic adenocarcinoma cells (the effect was reversible in the presence of mevalonic acid [201]), and human glioma cells which resulted from decreased farnesylation of Ras and abolishment of MAPK activity [202]. Analogous effects, caused by simvastatin, lovastatin and pravastatin, were observed in acute myeloid leukaemia, manifested by reduced growth of leukemic progenitor cells [203]. Cell migration. Besides antiapoptotic and growth-inhibitory properties, statins were also shown to repress cell migration and adhesion, decreasing the invasiveness and metastatic potential of several tumours. This effect primarily resulted from Rho delocalization. For instance, inhibition of RhoC by atorvastatin was responsible for the reduced metastasis in melanoma cells [204]. In the same manner, lovastatin reversed the invasive phenotype of mammary carcinoma mice model and reduced number of experimental lung metastases [205]. Lovastatin also attenuated the TNFα-induced expression of E-selectin, leading to decreased adhesion and invasion of human colon carcinoma cells [206]. Fluvastatin, in turn, diminished the EGF-stimulated pancreatic cancer cells invasion, affecting both, metastatic tumour formation in liver and growth of established liver metastases in mice [207]. The antimetastatic properties of fluvastatin were also confirmed in murine renal cancer cell Renca [200]. Of interest, as demonstrated in highly invasive, but not in poorly invasive, breast cancer cell lines, the statin-induced suppression of Rho geranylgeranylation caused disruption of actin fibres and

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disappearance of focal adhesion sites, correlated with downregulation of MMP-9 and urokinase, and final loss of cell attachment [199]. Angiogenesis. HMG-CoA reductase inhibitors also modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. In fact, statins were shown to reduce capillary formation by decreasing VEGF production on the one hand, and to increase proangiogenic effects by stimulation of VEGF, PKA and eNOS on the other hand [160]. It seems therefore plausible that the angiogenic activity of statins is cell- and concentration-dependent. Indeed, in one study, atorvastatin, simvastatin and lovastatin, at the concentrations ranging from 1-10 µmol/l, were found to reduce VEGF synthesis, but only in cells that released it abundantly. At the same time, cells that produced only small quantities of VEGF responded to statins presence by upregulation of VEGF [208]. Other research groups, in turn, found that low concentrations of statins (below 0,1 µmol/l) were proangiogenic due to activation of PI3K-Akt pathway and eNOS, while high concentrations (above 0,1 µmol/l) were antiangiogenic, and this effect was reversed by geranylated proteins, as shown for atorvastatin and cerivastatin [209,210]. Specifically, the mechanism behind the observed antiangiogenic effect of lovastatin (0,1-10 µmol/l) involved the inhibition of three RhoAdependent factors, i.e.: VEGF, Akt, and FAK [211]. Coagulation. A detailed discussion on the association between cancer and coagulation cascade will be the subject of the next paragraph. Here, however, it should be emphasized that statins exert antithrombotic activity that contributes to the modulation of the biology of several cancer types including melanoma. Particularly, atorvastatin and lovastatin, by decreasing prenylation of RhoA, reduced expression of the procoagulant protein – tissue factor (TF), causing the repression of thrombin that typically acts as a promoter of melanoma cells’ invasion [204].

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4.4. Specification of the statin-vulnerable malignancies

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Targeting cancer with inhibitors of HMG-CoA reductase seems to be an attractive anticancer approach, however, not all tumor types are vulnerable to such treatment. Clearly, as was the case in the previously-reviewed cardiology drugs, the utility of these agents needs a thorough examination in well-designed, randomized, controlled clinical trials. Nonetheless, given the results of available epidemiologic studies, statins appear to be useful in chemoprevention of: melanoma, breast, colon, uterine and prostate cancer. Furthermore, their growth-inhibitory, antiapoptotic, antimigratory potential provides clues for their repositioning in the adjuvant treatment of the following malignancies: melanoma, breast, colon, pancreatic, kidney cancer and acute myeloid leukemia. In addition, the standard cardiological dose regimens administered continuously, combined with conventional cytotoxic or biologic agents could provide the greatest therapeutic advantage. However, the selection of appropriate statin for clinical trials should be based on tumor type since no preference can be made judging from the reports discussed above.

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5. Heparin and LMWH The final group of cardiovascular system-related drugs with potentially untapped anticancer properties are heparin and its derivatives. Heparin is a biological drug with a well-established use in the treatment and prevention of venous thromboembolism [212], myocardial infraction and unstable angina [213]. This natural polymer belongs to the family of highly N-sulphated glycosaminoglycans, abundant in SO3- residues, which confer its negative charge [5]. Electrostatic properties of heparin determine its capability of non-specific interaction with other macromolecules in vivo, including adhesion molecules, chemokines or apolipoprotein E, contributing to its pleiotropic activity [214]. The cardinal biological function of heparin is interference with blood coagulation, which results from its 19

interaction with antithrombin (AT) and followed by abolishment of other components of coagulation cascade including: thrombin (IIa), Xa, IXa, XIa, and XIIa factors [212]. The described effect, especially with respect to thrombin, is highly structure-dependent, determined by the sufficient heparin chain length. Consequently, the pharmacologically improved heparin variants, with shorter polysaccharide chains, called LMWH, are deprived of the capability of thrombin inactivation, and hence, they are mainly targeted at Xa factor. This significant structural difference also adds to their altered behavior in the presence of other endogenous molecules typically interacting with heparin. Therefore, the pleiotropic effect of heparin and its derivatives, including the effect on cancer modulation is not equal for each agent, as demonstrated in further paragraphs.

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5.1. Role of coagulation in cancer

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Thrombosis and hypercoagulability are well-defined complications in malignancy. In fact, cancer patients are far more often affected by thromboembolic events when compared to non-cancer individuals, and their morbidity and mortality related to venous thromboembolism (VTE) is greater. For instance, the risk of preoperative deep venous thrombosis among cancer-affected population is two times higher [215,216], while the risk of recurrent VTE is three-fold increased when compared to cancer-unaffected subjects. Moreover, the manifestation of VTE is a negative prognostic factor associated with more aggressive character of the disease, as activation of coagulation cascade is believed to potentiate malignant tumor phenotype [217]. Thus, there is no surprise that heparin has been widely used in various types of neoplasia in the treatment and prophylaxis of VTE episodes. There are several exogenous risk factors contributing to hypercoagulability in malignancy, including: chemotherapy, radiotherapy, central venous catheters and immobility [214]. The primary reason for the cancer-related thrombosis, however, seems to have endogenous nature, manifested by the excessive activation of coagulation cascade secondary to neoplastic signaling, both of which are interdependent and cooperative by the principle of a positive feedback loop, as shown in Fig. 4. Specifically, this relationship explains a common coexistence of progressive cancer and VTE [218], displaying how cancer signaling exploits host coagulation system to promote its progression. The key mediator of this process is TF whose expression under physiological conditions is inducible, e.g. by inflammation, yet in mutated cancer cells, which upregulate it constitutively, it drives uncontrolled stimulation of platelets, and generation of thrombin and fibrin in cancer milieu [219]. Accumulation of fibrin, in turn, supports the formation of tumor stroma, as indicated by the fact that many solid tumors are abundant in various fibrinogen-derived products [220]. Fibrin also increases the release of TF and IL-8 from endothelium, leading to aggravated hypercoagulability and expression of adhesion molecules by circulating tumor cells, which provides them with the capability of interacting with platelets, leukocytes and endothelium [5]. Hence, the formation of tumor-fibrin-platelet clots occurs affording protection for malignant cells against host defenses. This effect, in turn, contributes to the maintenance of the propitious environment for their growth and invasion, thereby prolonging their intravascular survival. The complexes also support further blood clotting, stimulate platelet and leukocyte trafficking, and increase the ability of malignant cells to interact with the endothelial wall, discussed in detail later. On the other hand, increased local concentration of thrombin, induced by TF, activates platelets to release VEGF and platelet factor (PF-4) [220], which stimulates vascular smooth muscle cells to proliferation and migration, and supports formation of pathologic cancer vasculature [221]. As a positive feedback, the ongoing angiogenic process potentiates hypercoagulability by local production of IL-8 in endothelial cells as well as VEGF, TNF-α, IL-6, IL-1β in malignant cells [214]. 5.2. Preclinical and clinical data

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There is a great amount of literature data, including clinical trials, animal and in vitro studies, to confirm that heparins exert anticancer actions and could prolong patient survival. Such conclusions, however, have not been consistent across all the available reports, indicating that the significant heparin-dependent antineoplastic effect is context-specific and closely related to tumor stage. In fact, in the majority of available preclinical studies, the impact of heparins on the primary tumor was minimal [220]. Only in several reports a reduction of tumor mass was achieved, which probably resulted from a high dose of heparin derivative applied and a long-term treatment exceeding 15 days [222]. In this context, administration of heparins locally, into the peritoneal cavity, turned out to be effective in inhibiting the growth of the primary tumor, indicating that high concentrations of heparin around tumor are essential to significantly decline its development [223]. Hence, it is believed that modulation of the primary tumor biology is a secondary mechanism by which heparins exert their antineoplastic effects in vivo. On the other hand, studies evaluating the impact of heparins on the process of tumor spreading yielded more details on the putative mode of their anticancer activity. In fact, a significant attenuation of metastasis in melanoma, breast cancer, colon carcinoma and osteosarcoma was uncovered [216,224,225]. Interestingly, also chemically modified heparins, with decreased anticoagulant activity, showed antimetastatic properties [226], suggesting that the observed inhibition of tumor spreading resulted not only from attenuation of coagulation cascade but also from other, unrelated mechanisms. The hypothesis that heparins are primarily antimetastatic stays in agreement with available clinical data. In fact, in numerous human trials it was shown that survival benefit regarded mainly patients using LMWH at the initial stage of malignancy. For instance, in the FAMOUS study, subcutaneous injection of dalteparin at standard dose resulted in improved one-year survival in a subgroup of patients with good clinical prognosis when compared to placebo. Nonetheless, such effects did not occur in patients with advanced disease [227]. Furthermore, in the MALT double-blind study, in which the effect of nadroparin vs. placebo on survival in patients with advanced malignancy without VTE was evaluated, the six-week subcutaneous administration of the study drug favorably influenced clinical outcomes of subjects with life expectancy over six months [228]. Prolonged survival in patients with good clinical prognosis was also reported in the CLOT study, in which the efficacy of dalteparin vs dalteparin plus coumarin derivative in secondary prophylaxis of thrombosis in cancer patients was assessed [229]. Similarly, in the trial by Lee et al., the one-year mortality was significantly reduced in a subgroup of patients without metastatic disease receiving dalteparin for six months when compared to those receiving vitamin K antagonist. Of interest, in the general study population, involving patients at various stages of the disease, one-year mortality among dalteparin and vitamin K antagonist users was comparable [230]. Strikingly, improved survival of patients with advanced malignancy was also noted in several reports, for example in PROTECHT study examining the efficiency of nadroparin for thromboembolic prophylaxis. However, the effect was significant only in the subpopulation responding to chemotherapy [231]. Moreover, in the randomized clinical trials by Zhang et al., Antilabs et al. and Leumberri et al., improved clinical outcomes of patients with small cell lung cancer were observed after introduction of dalteparin 500 IU or bemiparin 3500 IU to standard chemotherapy [232–234]. In addition to this, in the comprehensive systemic review by Akl et al. a slight enhancement of survival rates in patients with mixed cancer types using LMWH-based anticoagulant therapy was found, however the routine administration of LMWH for survival benefit without indications for thromboprophylaxis was not recommended by the authors unless a thorough risk-benefit assessment was performed [235]. These conclusions seem to reflect a current doubtful attitue towards LMWHs repurposing to oncological indications. Finally, the superiority of LMWH over the unfractioned heparins (UFH) in cancer protection was reported in several clinical trials, confirmed by a subsequent meta-analysis [236,237]. For example, von Tempelhoff and Heilmann observed a reduction of mortality in patients receiving LMWH (5.7%) versus UFH group (15.6%)

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administered for 7 days after surgery for pelvic or breast cancer [238], while Hull et al. found that administration of LMWH was associated with lower total mortality by 51% when compared to UFH in cancer patients [239]. Despite these promising results, there are also numerous clinical trials in which the protective effect of heparins in cancer patients was not observed. These studies, however, were usually performed in patients with advanced metastases and poor prognosis [240], in which the heparin-related retardation of metastatic process was insufficient to achieve a significant clinical improvement. In line with this, a recent meta-analyses from 2014 by Sanford et al. showed no survival benefit among LMWH users with advanced solid tumors [241]. No correlation between LMWH and patient outcomes was also observed in specific tumours, including: NSCLC, hormone-refractory prostate cancer and locally advanced pancreatic cancer, as noticed by Zhang et al. [232]. In addition, in small cell lung cancer patients using supraprophylactic doses of enoxaparin with standard chemotherapy no survival gain was reported, although reduction of VTE risk occurred [242]. A number of clinical trials, with LMWH alone or in combination with chemotherapy in different populations of cancer patients, are also currently being conducted to explain the optimal heparin dosing regimens and subgroup of patients who would benefit from such treatment. Among these – PERIOP-01 study, investigating the influence of prophylactic, long-term use of tinzaparin on CRC reoccurrence or progression after surgical resection [241]. Also the TILT study in which the impact of tinzaparin on OS among patients with completely resected, localized NSCLC is being assessed [243]. PROSPECT-ONKO 004 study, in turn, is evaluating the efficacy of enoxaparin for the prophylaxis of VTE and the survival of patients with locally advanced or metastasized pancreatic cancer [244]. What is more, other still active and recruiting clinical trials evaluating the options for LMWH’ repurposing include the following protocols: enoxaparin with neoadjuvant chemoradiotherapy of non-metastatic esophageal cancer (NCT03254511), long-term tinzaparin after surgical resection of CRC (NCT01455831), heparin, dexamethasone, floxuridine plus CapeOx or Folfox6 in adjuvant setting after resection of liver metastases from CRC (NCT02529774) and desulphated heparin with standard induction and consolidation therapy for acute myeloid leukaemia (NCT02873338). 5.3. Putative mechanism of action

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The exact mechanism behind heparin-related anticancer action still remains not fully recognized. It is, however, believed that the preclinically and clinically observed anticancer effects could possibly be linked with pleiotropic properties of heparins, with the inclusion of the anticoagulant and coagulation-independent pathways which disturb cancer proliferation, angiogenesis, immune escape and metastasis. Coagulation-dependent mechanisms of anticancer action. The cardinal activity of heparin and LMWH is the suppression of coagulation cascade, the overexpression of which augments cancer malignancy. In this respect, the inhibition of coagulation enzymes, i.e.: IIa, Xa, IXa, XIa, and XIIa aborts the downstream signaling of TF, diminishing thereby production of thrombin and reducing deposition of fibrin and platelets around circulating cancer cells. This effect, in turn, increases the susceptibility of malignant cells to NK, reduces their capability of adhesion and abolishes their metastatic potential [220]. The preclinical studies with fibrinogen-deficient mice confirmed this assumption, showing that the accumulation of fibrinogen is essential for metastases formation, as animals mutated for its decreased expression developed less metastatic foci than the wild-type ones [245]. Furthermore, reduced local production of thrombin could downregulate thrombin receptors on the surface of malignant cells, aborting thereby mitogenic signal and decreasing the generation of VEGF, consequently impairing angiogenesis [246]. 22

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Besides this, heparins decrease the procoagulant activity of neoplastic cells by liberating tissue factor pathway inhibitor (TFPI) from vascular endothelium. This protein increases the rate of inactivation of FXa and TF-FVIIa complex and imposes final attenuation of the cancer-mediated hypercoagulability, causing suppression of tumor growth [220]. Interestingly, the efficiency of modulating TFPI release is not equal across known LMWH and it seems to depend on their molecular size, with tinzaparin being more potent than enoxaparin and UFH [247]. Finally, heparins also reduce thrombocytopenia in cancer patients. This beneficial effect is actually associated with their inhibition of two pathological processes, namely the aggregation of platelets, caused by excessive upregulation of platelet adhesion receptors on cancer cells (CD62, CD63, P-selectin), and the entrapment of platelets in tumor-fibrin clots [214,220]. A study with experimental mice sufficiently confirmed this relationship, since after intravascular inoculation of melanoma cells into animals a rapid decline in platelets count occurred, which was fully reversed after tinzaparin treatment [224]. Similar observations were made for enoxaparin, UFH and warfarin but not for modified non-anticoagulant heparins [248]. Coagulation-independent mechanisms of anticancer actions. To investigate the coagulation-independent mechanisms of heparins’ anticancer action, a series of modified heparins with decreased anticoagulant activity was developed, including: periodate-oxidized (IO4-) heparin, periodate-oxidized, alkaline degraded heparin (IO4- -LMWH), N-acetylated heparin, N-desulphated heparin, O-desulphated heparin, carboxyl-reduced heparin and N-succinylated heparin. All of them had a limited capability of interacting with AT, however they still exerted antiproliferative, antiangiogenic and antimetastatic actions. Thus, further investigations were performed to identify their molecular target in oncology [226]. Effect on metastasis. Based on available experimental and clinical data, heparins are thought to be mainly antimetastatic. In this context, the process of metastasis can be defined as an active and multistage cascade relying on the cross-talk between malignant cells and specific components of their environment. Pathophysiologically, it involves the following steps: detachment of neoplastic cells from parent tumor, invasion of host tissues and extracellular matrix, entering the bloodstream, dissemination, adherence to the endothelium of a new organ, extravasation and colonization. Interestingly, heparins are deemed to interfere with three of these processes, i.e.: selectins-mediated adhesion, chemotaxis and transmigration through the endothelial membrane, as demonstrated in Fig. 5. With this regard, the expression of adhesion molecules (integrins, selectins) on the surface of circulating neoplastic and endothelial cells is the primary aspect of this mechanism. In fact, these transmembrane receptors can form mutual strong bonds allowing malignant cells to dock to a new location [216,217]. The high adhesion capacity of circulating malignant cells is additionally enhanced by their altered surface glycosylation pattern, with increased expression of sialylated and fucosylated glycans (e.g. sialyl Lewis x and sialy Lewis epitopes) which in vivo can be recognized by endothelial E- and platelet P-selectins [220]. Thus, the so modified circulating cancer cells show increased tendency of aggregation with platelets via P-selectins, supporting their further anchoring to endothelium, which finally protects them from the host immune response. Interestingly, heparins were suggested to disrupt the interactions between L- and P-selectins and their ligands leading to the decay of the selectin-mediated complexes between cancer cells and platelets. This effect, in turn, can further suppress the process of neoplastic cells’ rolling, as confirmed in experimental studies involving animal models of metastases, with tinzaparin being more efficient than dalteparin and enoxaparin [225]. Likewise, heparins with no anticoagulant activity exerted anti-selectins actions, unlike a potent anticoagulant – fondaparinux [216,220], confirming no correlation with coagulation-dependent pathways in this mechanism. Once malignant cells become arrested by the target endothelium, they need to penetrate surrounding tissues to finally colonize distant organs and proliferate. This process is known as

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extravasation and it is facilitated by proteolytic enzymes, overexpressed by tumor cells, including MMPs and heparinase. Heparinase cleaves polymeric heparan sulphate proteoglycans, an important constituent of ECM and endothelial cell layer, while its upregulation in cancer cells appears to augment their malignant phenotype [5,216,220]. The activity of heparinase can be effectively inhibited by heparin and heparin derivatives, which experimentally results in suppression of metastatic process. This effect, however, refers only to the heparinase-expressing tumors, involving: breast, colon, ovary, bladder, pancreatic, lung cancer and myeloma [226,249,250], and therefore it cannot be regarded as the main mechanism of antimetastatic activity of heparins. Following extravasation, the directed chemotaxis of neoplastic stem cells to a new location occurs. This process is mediated by a special group of chemokines, normally responsible for leucocyte recruitment and migration. In neoplasia they are, however, significantly overexpressed by cancer stem cells. The primary molecular pathway implicated in this process is CXCL-12-CXCR4 axis [216], including C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184). In healthy tissues its expression is usually low or not present, yet in over twentythree cancer types, including breast, ovarian, melanoma, pancreatic and prostate cancer, its upregulation occurs. This effect potentiates tumors’ capability of invading tissues and organs, especially those containing high concentrations of CXCL12, including: lungs, liver and bone marrow [251]. Interestingly, heparins have been found in several experimental studies to disrupt the synthesis and function of these chemokines [252,253], causing interference with CXCL12-CXCR4 axis, abolition of chemotaxis and final suppression of cancer metastasis. This pathway, however, remains not fully recognized until now. Effect on angiogenesis. The mechanisms of heparin-induced anticancer activity also involve its capacity of antiangiogenic responses, experimentally exhibited by the LMWH-dependent reduction of microvessel density in several preclinical assays [254]. Of interest, enoxaparin, dalteparin, tinzaparin and UFH interfered with the FGF- and VEGF-induced proliferation of endothelial cells, however their efficiency varied across the studies [214,254]. At the molecular level, the observed effects could result from several mechanisms. One of them involves the LMWH-dependent suppression of VEGF/VEGFR interaction, secondary to their electrostatic properties [216], yet this hypothesis has not been fully elucidated until now. Furthermore, the antiangiogenic actions of heparins may stem from the release of endothelial TFPI or abolition of heparinase [214]. In the letter case, heparinase is known to release heparin sulphate (HS) groups from heparin sulphate proteoglycans (HSPGs), which serve as growth-factor-storing structures, especially for VEGF and bFGF. They also play a role of cofactors in the activation of the corresponding signal-transducing receptors. Curiously, soluble heparins competitively inhibit the interaction between HS and growth factors, decreasing thereby their affinity to receptors and ultimately leading to inhibition of angiogenesis [5,220]. Indeed, available in vitro experiments indicated that UFH and LMWH suppressed the bFGF-induced neovascularization, secondary to decreased interaction between HS and bFGF [255]. Nonetheless, this activity was attributed only to LMWH of less than 10 polysaccharide residues. LMWH of less than 18 residues inhibited also VEGF. The in vivo study confirmed these findings showing that LMWH, unlike UFH attenuate the VEGF and bFGF-driven angiogenesis in rat cornea [256]. Effect on cell proliferation. Although, dalteparin, tinzaparin and enoxaparin, unlike UFH, were shown in experimental studies to interfere with Ras/Raf/MEK/ERK signaling pathway, with dalteparin being the most potent [214,220], the insufficiency of data on this issue caused that inhibition of proliferation was not considered as the major determinant of heparin-induced anticancer efficiency. In conclusion, although a great investigational effort has been undertaken to elucidate the role of heparin in cancer management, the detailed description of the mechanism of action, optimal dosing

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and target population is still anticipated. For this reason heparins are still not recommended in cancer patients for survival improvement. 6. Conclusion

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Cardiovascular diseases and cancer are two most prevalent causes of mortality in humans. They also share a common ethiology, including: obesity, metabolic abnormalities, hyperglycaemia, hypercholesterolemia, insufficient physical activity, improper diet, nicotine, geriatric age, stress, etc. Thus, their coexistence is frequent and interdependent, as confirmed by a large study of seven European prospective cohorts, in which the association between hypertension and cancer was established, specifically in men with elevated blood pressure. In addition, an increased risk of overall cancer mortality was attributed to the general population of hypertensive patients [257]. Therefore, the interest on the potential link between cardiology drugs and cancer outcomes comes as no surprise. As reviewed in this paper, several groups of typical cardiovascular system-related agents were actually reported to exert antineoplastic effects under specific circumstances. Thus, it is possible that their rational use could actually facilitate cancer management, especially in cardio-oncological patients. Based on the discussed results, the greatest potential for successful repurposing have anti-RAAS agents, specifically as adjuvants to anti-angiogenic therapies. Second in the scope of repositioning are non-selective BBs as sensitizers to trastuzumab and as adjuvants in ovarian cancer and melanoma. Statins, in turn, seem to be more associated with chemoprevention (e.g. in CRC) based on the fact that the mevalonate pathway is not targeted by cancer adaptative mechanisms. However the adjuvant treatment of breast cacer by several anti-HMG-CoA reductase inhibitors could be also probable. The concept of nano-carriers for statins delivery also deserves a thorough clinical attention. Finally, the potential of LMWH is less obvious, mainly because of the unfavourable results of meta-analysis by Akl et al [205]. Notwithstanding the assumptions presented above, it is important to emphasise that the inconsistency of clinical data exists for each discussed class of drugs. Therefore, despite the intense investigational effort to clearly elucidate the liable cancer contexts, our capacity to translate it into clinical success appears insufficient. It is beyond dispute that the properly-designed, targeted clinical trials are still in their infancy and hence, fully reliable data is currently lacking. Nonetheless, although available results only highlight a trend demanding definitive verification, they might influence the process of decision making in cancer patients with concomitant cardiological disorders. The suggestions demonstrated in this article are far from being recommendations, yet they indicate the direction for clinical trials design.

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Conflict of interest

The authors declare no conflict of interest.

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Conflict of Interest Statement

This statement regards the article entitled: Beyond the boundaries of cardiology: still untapped anticancer properties of the cardiovascular system-related drugs

Hereby, on behalf of all the Authors I declare no conflict of interest.

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Katarzyna Regulska, Ph. D. Greater Poland Cancer Center Garbary 15 Strr, 61-866 Poznan Poland

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molecules to exert a multitude of anti-inflammatory activities., Mini Rev. Med. Chem. 6 (2006) 1009–1023. doi:http://dx.doi.org/10.2174/138955706778195180. H. Takahashi, S. Ebihara, T. Okazaki, M. Asada, H. Sasaki, M. Yamaya, A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity, Br. J. Pharmacol. 146 (2005) 333–343. doi:10.1038/sj.bjp.0706344. A. Collen, S.M. Smorenburg, E. Peters, F. Lupu, P. Koolwijk, C. Van Noorden, V.W. van Hinsbergh, Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro., Cancer Res. 60 (2000) 6196–6200. http://www.ncbi.nlm.nih.gov/pubmed/11085545. A. LEPRI, U. BENELLI, N. BERNARDINI, F. BIANCHI, M. LUPETTI, R. DANESI, M. DEL TACCA, M. NARDI, Effect of Low Molecular Weight Heparan Sulphate on Angiogenesis in the Rat Cornea After Chemical Cauterization, J. Ocul. Pharmacol. Ther. 10 (1994) 273–280. doi:10.1089/jop.1994.10.273. T. Stocks, M. Van Hemelrijck, J. Manjer, T. Bjorge, H. Ulmer, G. Hallmans, B. Lindkvist, R. Selmer, G. Nagel, S. Tretli, H. Concin, A. Engeland, H. Jonsson, P. Stattin, Blood Pressure and Risk of Cancer Incidence and Mortality in the Metabolic Syndrome and Cancer Project, Hypertension. 59 (2012) 802–810. doi:10.1161/HYPERTENSIONAHA.111.189258.

42

IP T SC R U

A

CC E

PT

ED

M

A

N

Figure 1. The impact of ANG II on promotion of carcinogenesis and molecular targets of ACE-I’s anticancer action.

43

IP T SC R

A

CC E

PT

ED

M

A

N

U

Figure 2. The mechanisms of SNS-mediated cancer development.

Figure 3. The mechanism of statins’ anticancer action.

44

IP T SC R U

A

CC E

PT

ED

M

A

N

Figure 4. The relationship between blood clotting and cancer cells survival.

Figure 5. The mode of heparins’ antimetastatic activity.

45

Table 1. Summary of ARB’s clinical data. Drug

CHARM-Overal

Candesartan Significantly increased (42%) risk of developing fatal cancer in candesartan group vs placebo.

[72]

LIFE

Losartan

Increased risk of malignancy in losartan group by 12% vs control; the risk was even greater in case of lung and prostate cancer.

[73]

ONTARGET

Telmisartan

Non-significantly increased incidence of cancer among telmisartan patients by 9%; however the significantly higher risk of neoplasia was reported for those taking a combination therapy of telmisartan and ramipril when compared to ramipril alone.

[74]

TRANSCEND

Telmisartan

The risk of neoplastic diseases was higher by 16% among telmisartan users when vs placebo.

[75]

PRoFESS

Telmisartan

Non-significantly increased incidence of lung cancer (24%), prostate cancer (12%), and breast cancer (36%).

[76]

VALIANT

Valsartan

Higher cancer-associated mortality in valsartan group [77] (22%) when compared with captopril group.

VALUE

Valsartan

Significant 15% decrease in neoplastic diseases in the [78] ARB group.

Coleman, 2008 (RENAAL, CHARM, LIFE and TROPHY studies)

All

Insignificant impact on cancer incidence, the trend was [79] unfavorable and more pronounced than in other antihypertensive drugs.

Ref

SC R

U

N

A

M

ED

PT All

Modestly increased and significant absolute risk of new [80] cancer occurrence associated with ARB treatment, especially for lung cancer (the increase by 25%). The insignificant relationship found between ARBs and the prostate (7-32%) and breast cancer (4%).

ARB Trialist All Collaboration, 2011

No correlation between ARBs generally and cancer. The [81] insignificant increase of malignancy associated with candesartan, losartan, and telmisartan, while the significantly decreased risk of cancer for valsartan, and non-significantly decreased for irbesartan.

A

CC E

Sipahi et al., 2010 (LIFE, CHARM, ONTARGET, ProFESS and TRANSCEND

Result

IP T

Study

Pasternak 2011

et

al, All

ARBs not significantly associated with increased risk of incident cancer overall or of lung cancer.

[82]

46

Bhaskaran et al., All 2012

No significant correlation between cancer incidence generally and ARBs. For individual tumor types: significantly lower incidence of lung cancer with ARB therapy, significantly higher risk of breast and prostate cancer for ARBs vs ACE-Is.

[83]

Zhang et al., 2015

ARB was significantly associated with decreased LC risk in Asians and no risk in Caucasian race.

[84]

A

CC E

PT

ED

M

A

N

U

SC R

IP T

All

47

Table 2. Summary of clinical data for BBs’ anticancer action Result

Breast cancer

Atenolol, propranolol, bisoprolol, timolol

Reduced metastasis and Epidemiological, retrospective; 466 tumor recurrence; longer BBs users vs. other disease free interval antihypertensives users vs. normotensive subjects

[107]

Breast cancer

Propranolol, atenolol

Less advanced disease, Epidemiological, retrospective; 5333 reduced cancer mortality hypertensive propranolol users in propranolol group vs. vs. atenolol users vs. nonusers nonusers or atenolol users.

[111]

Breast cancer

Metoprolol, atenolol, propranolol, other

Improved relapse-free Epidemiological, retrospective; survival but not overall BBs users vs. nonusers survival

1413

[112]

Breast cancer

All

BBs use not associated Population-based, case-control, 1247 with the risk of breast observational; subjects using cancer incidence commonly prescribed medications vs. nonusers

[113]

Breast cancer

All

No association between Epidemiological, 654 BBs and breast cancer observational; Breast cancer, hypertensive female vs. hypertensive female without cancer history

[114]

Melanoma

All

Reduced progression Observational, prospective; 121 after exposure to BBs for BBs users vs. nonuser at least 1 year

[115]

Melanoma

Metoprolol, propranolol, atenolol

Increased survival after use for more than 90 days; increased mortality after less than 90 days use compared to nonusers

Population-based cohort study; 4179 BBs users for less than 90 days prior to melanoma diagnosis vs. BBs users for more than 90 days vs. nonusers

[116]

Atenolol, propranolol, other

Poorer survival in BBs Population-based retrospective 3462 users cohort study; BBs users vs. other antihypertensives

[117]

Number Ref of patients

SC R

U

N

A

M

ED

PT

CC E A

Pancreatic, prostate, stomach

Study type

IP T

Cancer type LBA

48

Lung, breast, colorectal

As above

No influence on survival

As above

Lung cancer

All

No association reduced mortality

Lung cancer

All

improved DMFS, DFS, Retrospective and OS in patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy

[117]

3340

[118]

722

[119]

IP T

with Population-based cohort study

3462

Increased risk of disease Epidemiological, retrospective; 335682 compared to nonusers antihypertensives users vs. nonusers

[120]

Prostate

Only BBs reduced risk Retrospective, case-control 13326 of prostate cancer, unlike study; antihypertensives users ACE-I and calcium vs. nonusers channel blockers

[121]

N

U

SC R

Renal cell All cancer

All

54% reduced chance of Institutional death compared with of review non-users.

retrospective 248

[122]

All types

Metoprolol, bisoprolol, acebutolol, atenolol, propranolol

BBs reduced cancer Prospective, observational; 839 incidence when patients with cardiovascular compared to other disease using BBs users vs. antihypertensives other antihypertensives

[123]

All types

Carvedilol

Long-term treatment Population-based cohort study associated with reduced upper gastrointestinal tract and lung cancer risk

[124]

6771

A

CC E

PT

ED

M

A

Ovarian

49

Table 3. Summary of preclinical data behind BBs’ anticancer activity – mechanism of action BBs

Mechanism of action

Effect

Propranolol, nadolol

Downregulation of cAMP/PKA,

Reduced angiogenesis and Breast metastasis, no effect on primary tumor

decrease of TAMs recruitment

Cancer type

Ref [129]

Propranolol

Inhibition of GROα release from Reduced adhesion human pulmonary microvascular metastasis endothelial cells. GROα causes a β1integrin-mediated increase of adhesion

Propranolol

Decreased cAMP/PKA, reduced Increased apoptosis, Ovary VEGF, basic fibroblast growth factor decreased tumor growth, (bFGF), MMP-2 and MMP-9 angiogenesis and migration

[108]

Propranolol

Decreased VEGF

Reduced tumor growth Ovary and microvessel density

[131]

Propranolol

Reduced NE-induced FAK activation

Reduced anoikis

Ovary

[101]

Propranolol

Reduced MMP-9 and MMP-2

Reduced invasiveness

Ovary

[132]

Propranolol

Reduced BAR/cAMP/PKA/SRC

Reduced invasiveness, Ovary migration and growth

[133]

Propranolol

Reduction of NE-induced IL-8 and Reduced angiogenesis, Ovary FosB mediated by PKA invasion, migration, no effect on proliferation

[134]

Propranolol

Reduction of NE-induced STAT3, Reduced reduction of MMP-2 and MMP-9 invasion

and Ovary

[135]

Propranolol

Reduced tumor cell clearance, Reduced postoperative Breast increased NK cytotoxicity immunosuppression and metastatic progression, increased recurrence-free survival

[109]

IP T

[130]

SC R

U

N

A

M

ED

PT

CC E A

Propranolol Increased expression of Fas ligand and plus etodolac CD11a, increased NK cytotoxicity, increased lymphocyte concentrations, and decreased corticosterone levels after surgery, no effect on VEGF expression Propranolol

and Breast

growth

Improved recurrence-free Melanoma, survival in mice undergoing primary tumor lung excision

Reduced arachidonic acid-related Reduced proliferation mitogenic signal transduction

[136]

Lung

[137]

50

Atenolol

involving COX- and lipoxygenasedependent messengers. Reduced MMP-2, MMP-9 and VEGF

Reduced angiogenesis and Nasopharyngx invasion

Propranolol

No impsct on cAMP signalling, Reduced tumor growth, Leukaemia probable impact on immune cells or metastasis the bone marrow microenvironment

[95]

Propranolol

Upregulation of the potent cell cycle Reduced proliferation, Hemangioend inhibitors; Cdkn1a and Cdkn1b, enhanced apoptosis othelioma and angiosarcoma decreased proliferative marker PCNA decreased key cell cycle regulators: Cdk4, Cdk6, cyclin D1, and cyclin E1

[139]

ICI118,551

Reversed epinephrine-induced Increased apoptosis phosphorylation BAD by cAMPdependent protein kinase

Prostate, breast

[140]

ICI118,551

Inactivation of ADRB2/PKA/BAD pathway

Prostate, breast

[141]

U

SC R

Propranolol

IP T

ICI118,551

A

N

EPI-induced Increased apoptosis antiapoptotic

M

ICI118,551 atenolol

ED

Propranolol

Antimigratory effect – Prostate atenolol partial, ICI118,551 - complete

[142]

Antimigratory, antimetastatic effect

[143]

Decreased MMP-2, MMP-9, VEGF

Propranolol

Reduced CERB, NF-κB, AP-1, MMP- Reduced invasion 2, MMP-9, COX-2 and VEGF; proliferation reduced PKA/cAMP and MAPK

CC E

PT

Propranolol

Metoprolol

[138]

Inhibition of cAMP/PKA

Prostate

Reduced proliferation, Pancreas migration, invasion

Supressed invasion

and Pancreas

[145]

Pancreas

[145]

NE-induced Colon

[146]

A

Propranolol Reduced β-arrestin/srcPTK/ Reduced but not phospholipase C γ (PLC γ) migration atenolol /diacylglycerol (DAG)/PKCα

[144]

Atenolol ICI 118,551

Abrogated EPI-induced COX-2, Reduced growth VEGF, MMP-9 and prostaglandin PGE2

Colon

[147]

51

Propranolol

Reduced NNL-induced COX/PGE2

Antiproliferatory, reduced Stomach cell growth

Propranolol

Reduced PKC/ ERK1/2/COX-2/PGE2 Reduced proliferation pathway

[148]

Stomach

[149]

cell Stomach increased

[150]

Atenolol ICI 118,551 G0/G1 and G2/M cell cycle arrest, Inhibited decreased NF-κB, downregulated proliferation, VEGF, COX-2, MMP-2 and MMP-9 apoptosis

Propranolol

Reduced gene expression for VEGF and IL-8 , IL-6 release

Reduced angiogenesis, Melanoma reduced activation of stromal and inflammatory cells of melanoma microenvironment

[151]

Propranolol

Induction of ERK 1/2, reversed Reduced proliferation, Melanoma recruitment of mesenchymal stem reduced activation of cells stromal and inflammatory cells of melanoma microenvironment

[152]

Propranolol

Reduced MMP-dependent motility, Reduced invasion, Melanoma reduced IL-6, IL-8 and VEGF, migration, angiogenesis Decreased MMP-9 and MMP-2

[153]

ICI 118,551

G0/G1 cell cycle arrest associated Reduced cell proliferation Hemangioma with decreased cyclin D1, CDK-4, and apoptosis CDK-6 and phospho-Rb

[154]

M

ED

metoprolol

A

N

U

SC R

IP T

Propranolol

Reduced cell proliferation

Breast, melanoma, cervix, leukaemia

[155]

A

CC E

PT

Carvedilol

52

Table 4. Statins-dependent prevention of malignancies - summary of clinical results Statin

Effect

Reference

Melanoma

Lovastatin

50% reduced incidence

[169]

Colorectal

All

47% reduced incidence

[170]

Breast

All

72% reduced incidence

[171]

Uterine

All

70% reduced incidence

[172]

Prostate

All

56% reduced incidence

All cancers

All

20% reduced incidence

IP T

Cancer type

[173]

A

CC E

PT

ED

M

A

N

U

SC R

[174]

53