Angiomodulators in cancer therapy: New perspectives

Biomedicine & Pharmacotherapy 89 (2017) 578–590

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Original article

Angiomodulators in cancer therapy: New perspectives Lenka Varinskaa,1, Peter Kubatkab,c,1,** , Jan Mojzisa , Anthony Zullid, Katarina Gazdikovae,f,*** , Pavol Zuborc,g , Dietrich Büsselbergh , Martin Caprndai, Radka Opatrilovaj, Iveta Gasparovak , Martin Klabusayl , Martin Pecb , Eitan Fibachm , Mariusz Adamekn , Peter Kruzliakj,* a

Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia d The Centre for Chronic Disease, College of Health & Biomedicine, Victoria University, Melbourne, Werribee Campus, Victoria, Australia e Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovak Republic f Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovak Republic g Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia h Weill Cornell Medicine in Qatar, Qatar Foundation-Education City, Doha, Qatar i 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia j Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho tr. 1/1946, 612 42 Brno, Czechia k Institute of Biology, Genetics and Medical Genetics, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovak Republic l Department of Haemato-Oncology and Department of Internal Medicine – Cardiology, Faculty of Medicine, Palacky University, Olomouc, Czechia m Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel n Department of Thoracic Surgery, Faculty of Medicine and Dentistry, Medical University of Silesia, Katowice, Poland b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 24 November 2016 Received in revised form 3 February 2017 Accepted 20 February 2017

The formation of new blood vessels plays a crucial for the development and progression of pathophysiological changes associated with a variety of disorders, including carcinogenesis. Angiogenesis inhibitors (anti-angiogenics) are an important part of treatment for some types of cancer. Some natural products isolated from marine invertebrates have revealed antiangiogenic activities, which are diverse in structure and mechanisms of action. Many preclinical studies have generated new models for further modification and optimization of anti-angiogenic substances, and new information for mechanistic studies and new anti-cancer drug candidates for clinical practice. Moreover, in the last decade it has become apparent that galectins are important regulators of tumor angiogenesis, as well as microRNA. MicroRNAs have been validated to modulate endothelial cell migration or endothelial tube organization. In the present review we summarize the current knowledge regarding the role of marine-derived natural products, galectins and microRNAs in tumor angiogenesis. © 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Angiogenesis Anti-angiogenics Cancer therapy Marine natural products Galectins microRNAs

Contents 1. 2.

Introduction . . . . . . . . Marine-derived natural Bastadin 6 . . . . 2.1. 2.2. Aeroplysinin-1 .

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* Corresponding author. ** Corresponding author at: Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4, 03601 Martin, Slovakia. *** Corresponding author at: Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Limbova 12, 833 03 Bratislava, Slovak Republic. E-mail addresses: [email protected] (P. Kubatka), [email protected] (K. Gazdikova), [email protected] (P. Kruzliak). 1 Co-First/Equal authorship. http://dx.doi.org/10.1016/j.biopha.2017.02.071 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

L. Varinska et al. / Biomedicine & Pharmacotherapy 89 (2017) 578–590

2.3. 2.4. 2.5. 2.6. 2.7. 2.8. 2.9.

3.

4.

Fascaplysin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frondoside A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philinopsides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fucoidans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fucoxanthin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trabectedin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The clinical use of marine-derived agents against cancer . . . . . . . . . . . . Trabectedin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9.1. 2.9.2. Cytarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eribulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9.3. Brentuximab vedotin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9.4. 2.9.5. Fludarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New potential therapeutic targets for angiogenesis – galectins and microRNAs Galectins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. microRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Products derived from plants have been used to treat human disease since the dawn of medicine. In our modern era, natural products are the foundation in drug discovery because many useful drugs (e.g. morphin, penicillin or aspirin) have been isolated and developed from nature. For example, in the field of oncology, almost 50% of the antitumor agents approved in the last 50 years of the 20th century were compounds derived from plants, animals or microbes [1,2]. It is well known that phytochemicals present in fruits and vegetables may modulate several steps in carcinogenesis [3]. Numerous potential mechanisms have been proposed for this cancer-preventing activity of phytochemicals such as induction of apoptosis, inhibition of signal transduction pathways (e.g. MAPK, PKC, PI3K, PTK, Akt, NF-kB) or scavenging of free radical [4,5]. Moreover, since the discovery in the early 1970s that tumor progression is angiogenesis–dependent [6], drugs with antiangiogenic effect started to play a role in cancer treatment, and recently they became a standard part of complex antitumor treatment. Formation of blood vessels is a complex process regulated by many cytokines and growth factors. Among them, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF) system, and hypoxia inducible factor (HIF-1) play key roles in stimulation of endothelial cell proliferation. Angiopoietins are another set of growth factors that regulate endothelial cell survival and interactions with supporting cells. Proangiogenic signaling is further regulated by extracellular matrix (ECM), including matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). These pathophysiological mechanisms led to using drugs which either inhibit proangiogenic factor activity (e.g. VEGF receptor inhibitors) or so far experimental use agents negatively regulating angiogenesis. At this place, we name the most commonly used drugs in cancer treatment which regulate angiogenesis. These drugs can be related to several categories: VEGF acting drugs – anti-VEGF monoclonal antibodies (bevacizumab), anti-VEGF receptor antibodies (ramucirumab) or soluble fusion proteins composed from receptor components of VEGFR1 and VEGFR2 fused to the human antibody (aflibercept); tyrosine kinase inhibitors (TKIs) – sorafenib, sunitinib, pazopanib, axitinib, regorafenib; epidermal growth factor (EGF) receptor inhibitors (erlotinib, gefitinib); immunomodulatory drugs (thalidomide, lenalidomide); and

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other agents with different mechanisms of actions which are under development or used within clinical trials. Phytochemicals has also been studied intensively for their ability to modify some steps in cancer angiogenesis. Today, it is known that many phytochemicals exhibit antiangiogenic activity [7–15], and the search for novel compounds continues. The molecular targets of selected promising natural antiangiogenic compounds are summarized in Table 1. The sea has been shown to be the source of plethora different molecules with various structures and promising biological activities. In contrast to ‘terrestrial nature’, marine organisms do not have a significant history of use in traditional medicine and the serious systematic investigation of marine environments as sources of novel biologically active agents only began in the mid-1970s [16]. To date, only few marine-derived drugs (trabectedin, cytarabine, fludarabine, eribulin, vedotin) have been approved by the FDA or EMEA registered for the cancer treatment [17]. Compared with drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles [18]. On the other hand, several other marine natural compounds are being evaluated in different phases of trials for the treatment of various cancers. Furthermore, more than forty marine-derived natural products, or their derivatives, have been reported to display antiangiogenic activities and more than half of them entered Phase I–IV clinical trials for cancer therapy [2,18]. The marine-derived antiangiogenic agents have various sources including marine animals (e.g. sponge, sea cucumber), microorganisms (e.g. fungi, bacteria) or algae [19]. The antiangiogenic properties and molecular targets of selected promising marine compounds are discussed later and summarized in Table 2. In recent years, it has become described that galectins can contribute to endothelial cell activation as well as to other steps of the angiogenesis cascade. This has identified galectins as potential target molecules for anti-angiogenic cancer therapy. Galectins have a wide range of biological functions in several physiological processes and in pathological conditions such as pre-eclampsia, inflammation, diabetes, and atherosclerosis [20–23]. Their expression is also correlated with cancer aggressiveness and metastasis. These findings have direct implications for current efforts on galectin-targeted cancer or angiostatic therapies. Posttranscriptional regulation by miRNAs in the cell is important for many aspects of organism development, homeostasis, and disease (including cancer). MicroRNAs (miRs) as new

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Table 1 Anti-angiogenic effects of selected plant-derived compounds. Phytochemicals

Possible mechanism

Reference

Quercetin

Inhibition of VEGFR2 expresion; inhibition of ERK signaling pathway; modulation of AKT/mTOR/P70S6K signaling pathways; inhibition of COX-2 expression; down-regulation the levels of Hsp90 and Hsp70, HIF-1a and VEGF; decreased secretion of MMP-2 and MMP-9 Inhibition of Smad2/3 and Src/FAK/Akt pathways; inhibition of IL-6/STAT3 pathway; Modulation of ERK-NFkB-cMyc-p21-VEGF pathway; inhibition of VEGF expression through both HIF-dependent (Akt/ HIF) and HIF-independent (ESRRA) pathways downregulation of HIF-1a and VEGF expression; suppression of VEGFC/VEGFR2, inhibion of ERK activation; inhibition of PI3K/Akt/mTOR signaling pathway Inhibition of Akt- and MAPK-driven HIF-1a basal expression; stimulation of the proteasomal degradation of HIF-1a; suppression of ROS-mediated NF-kB-dependent MMP-9 and COX-2 expression; inhibition of Akt phosphorylation; inhibition of VEGF/VEGFR2; Inhibition of VEGF-stimulated NO production; suppression of bFGF-stimulated COX-2 induction Suppression of MMP-9 transcription via inhibition AP-1 and NF-kB activity; inhibition of basal VEGF and hypoxiastimulated VEGF expression; down-regulation of EGF and IGF; inhibition of PTK activity and MAPK activation; decrease in MMPs production and activity; inhibition of expression/excretion of proangiogenic factors - MMPs, PDGF, TF, uPA, VEGF; up-regulation of angiogenesis inhibitors TSP-1, - PAI-1, endostatin, angiostatin; downregulation of HIF-1a and VEGFA expression; suppression of VEGF, MMP-2, MMP-7 and ICAM-1 expression; increased expression of TIMP-2; suppression of NF-kB activation; Inhibition of VEGF-induced p38 MAPK, p125(FAK) and AKT activation, inhibition of STAT3 activation Suppression of NF-kappaB and Akt pathways; reduced VEGF secretion; inhibition secretion of MMP-9, uTPA and VEGF-A; inhibition of NF-kB activation; inhibition of VEGFR2 signaling pathways, including ERK1/2, p38, and PI3K-AKT; inhibition of MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways; Inhibition of MMP-2 and MMP-9 gelatinolytic activity Inhibition of HIF-1a and STAT3 binding to VEGF promoter; inhibition of prolidase, HIF-1a and VEGF expressions, and inhibition of collagen biosynthesis; Inhibition of NF-kB activation; Suppression of AKT/mTOR/P70S6K pathway; decrease in nuclear HIF-1a protein level; suppression of VEGFR-1 and VEGFR-2 receptors expression; Inhibition of the MEK/ERK and PI3K/AKT pathways; inhibition of hypoxia-induced VEGF, HIF-1a and c-Myc mRNA expression; decrease in VEGF expression via HIF-1a inhibition; inhibition of the PI-3K/AKT pathway; inhibition of pro-angiogenic factors such as HIF, VEGF, COX-2, NO, NF-kB; downregulation of VEGF mRNA expression; inhibition of MMP2 VEGFR-1 inhibition, inhibition of MMP-2 expression; decreased binding of VEGF to VEGFR1/Flt-1 Decrease in NF-kB, VEGF, MMP-2, MMP-9, and eNOS expression; inhibition of VEGFR phosphorylation; suppression of the phosphorylation of ERK1/2 inhibition of Ang-1, PDGFB and MMP2 expression, suppression of VEGFR2 phosphorylation, block of VEGFR2-mediated ERK1/2 signaling pathway Suppression of VEGFR2-mediated AKT and ERK1/2 signaling pathways

[149–153]

Apigenin Kaempferol EGCG Resveratrol

Genistein

Curcumin Capsaicin Xantohumol Licochalcone E Lycopene

betulinic acid Celastrol Sulforaphane Berberine farnesiferol Emodin Tryptanthrin Usnic acid

molecular regulators have been identified in endothelial cells, and their role in the regulation of different aspects of the angiogenesis has been recently investigated. Recently, a new group of miRs, called angiomiRs and hypoxamiRs, such as miR-15b-16, -17–92, -21, -126, -93, -100, -130, -132, -143–145, -210, -221–222, -296, -320, -378, -424, and Let7 family, have been validated to modulate the angiogenic process [24–26]. Many of these inhibitors of angiogenesis are now entering clinical trials, and several achieving approval for clinical use. On the other hand, major limitations have been reported by clinical evaluations. For instance, it includes resistance, enhancing tumor hypoxia and reducing delivery of chemotherapeutic agents, which might be the main reason for poor improvement in overall survival after the treatment with angiogenesis inhibitors in patients. From these reasons, the optimal settings of anti-angiogenic therapy become crucial for clinical practice [27]. This review provides most recent overview of marine-derived natural products based on their potential distinct mechanisms of action and molecular targets for angiogenesis. Moreover, this review summarizes the recent advances in our knowledge on the role of galectins and microRNAs in tumor blood vessels formation. 2. Marine-derived natural products Most of the compounds derived from marine sources are evaluated intensively in both preclinical and clinical anticancer research. Some preclinical investigated compounds – bastadin 6,

[154,155] [156,157] [158–160] [161–165]

[166–170]

[171–173] [174,175] [176,177] [178] [179–181]

[182,183] [184–187] [188–190] [191–194] [195,196] [197–199] [200] [201]

aeroplysinin-1, fascaplysin, frondoside A, philinopsides, fucoxanthin, or trabectedin are discussed in the following section of the article. 2.1. Bastadin 6 About thirty bastadins have been isolated so far and some of them have attracted wide attention due to their biological activities [28,29]. Bastadins have been reported as one the important class of anticancer agents. In particular bastadin 6, seems to be a promising natural lead compound for the development of marine natural product-based anticancer therapeutic agents [30]. Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, isolated from a marine sponge Ianthella basta, displayed in vitro cytostatic/cytotoxic effects in human and mouse cancer cell lines [31,32]. Moreover, it was found that bastadin 6 may also influence some steps in angiogenesis. Aoki and co-workers (2006) documented its ability to inhibit VEGF- or bFGF-dependent proliferation of HUVECs at nanomolar concentrations [33]. Bastadin 6 also inhibited VEGF-induced tubular formation and migration HUVECs. Moreover, it significantly blocked in vivo neovascularization in the mice corneal assay [33]. Later, Kotoku et al. revealed that oxime- and brominemodification of bastadin 6 play an important role to show the potent and selective anti-proliferative activity against HUVECs [34].

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Table 2 Anti-angiogenic effects of selected marine-derived compounds. Source

Examples

Biological effect

Reference

Sponge

Bastadin Cortistatins

Inhibition of VEGF- or bFGF-induced HUVECs proliferation, tubular formation and HUVEC mogration Inhibition of VEGF-induced migration of HUVECs and bFGF-induced tubular formation; in vitro and in vivo nhibition of VEGF-induced HUVECs migration Inhibitory effects of on endotheliala cell proliferation and differentiation; decreased concentration of MMP-2 and urokinase, dose-dependent inhibitory effect on the in vivo chorioallantoic membrane assay and Matrigel plug assay In vitro and in vivo inhibition of endothelial cells proliferation, migration and tube formation, inhibition of PKCa translocation Inhibition of HIF-1 signaling pathway MMP-1, -2, -8, -9, -12, and -13; inhibition of BAE cells migration Inhibition of VEGF-induced cell proliferation, migration and tube formation in the HUVEC, suppression of capillary-like structure formation, suppression of VEGF-induced expression of MAPKs and PI3K/AKT/mTOR signaling pathway. Inhibition of proliferation, migration and tube formation of HUVECs Selective inhibition of endothelial cells proliferation towards tumor cells, inhibiton of VEGF expression and secretion, inhibition of angiogenesis in CAM assay; cell cycle arrest and apoptosis in HUVEC.

[33,34] [131,132]

Aeroplysinin-1

Spongistatin1 Mycothiazole Ageladine A 6"debromohamacanthin A smenospongine Fascaplysin

Sea cucumber Frondoside A

Philinopside E

Philinopside A

[37,38]

[133] [134] [135,136] [137]

[138] [45,47]

Reduction of microvessel density in the xenografted tumor, significant decrease in bFGF-induced angiogenesis in [50,52] the CAM angiogenesis assay; inhibition of MMP-9 activity, reduced activation of AP-1 and NF-kB, and enhanced expression of TIMP-1 and TIMP-2. [54,55] Inhibition proliferation of HMECs and HUVECs, induction of endothelial cell apoptosis, suppression of cell migration, cell adhesion and tube formation in HMECs and HUVECs, inhibition of VEGF receptor 2 signaling; interaction with KDR extracellular domain, suppression of avb3 integrin-driven downstream signaling Inhibition of proliferation, migration and tube formation of HMECs, inhibition of angiogenesis in CAM assay, [53] inhibition of VEGF, FGF PDGF and EGF receptor signaling patways

Fungi

AD0157 Toluquinol

Inhibition of endothelial cells proliferation, differentiation and migration, inhibition of Akt signaling pathway Inhibition of capillary tube formation on Matrigel and migratory, invasive and proteolytic capabilities of endothelial cells, suppression of the VEGF and FGF-induced Akt activation

[139] [140]

alga

SargA Fucoidans

Significant decrease in bFGF-induced angiogenesis in the CAM angiogenesis assay and Gelfoam plugs assay Inhibition of bFGF-induced tube formation by HUVECs; inhibition of cell proliferation, cell migration, tube formation and vascular network formation, reduced expression of VEGF-A; suppression of MMP-2 and MMP-9 activity Suppression of mRNA expression of FGF-2 and its receptor FGFR-1, down-regulation of ERK1/2 and Akt phosphorylation; suppression of HUVEC proliferation and tube formation Inhibition of MMP-2, -9 expression and activity, inhibition molecules of MAPK pathway - MEK, ERK, and p38 Suppression of proliferation and tube formation by HUVEC, supression of ex vivo microvessel formation

[141] [61,62,148]

Fucoxanthin fucodiphloroethol G siphonaxanthin Miscellaneous Streptochlorin Aplidine SIP-SII

[70,71] [142] [143]

Inhibition of VEGF-induced endothelial cell invasion and tube formation, inhibition of TNF-a-induced NF-kB [144] activation Inhibition of VEGF and FGF-2-induced angiogenesis in the CAM angiogenesis assay, inhibition of VEGF- and FGF-2- [145] induced endothelial cell proliferation, migration and invasiveness, decrease in MMP-2 and MMP-9 secretion Inhibition of bFGF-induced angiogenesis in the CAM angiogenesis assay; inhibition of MMP-2 expression [146,147]

2.2. Aeroplysinin-1 Aeroplysinin-1 is a 1,2-dihydroarene-1,2-diol produced by Verongida sponges activated after tissue injury to protect them from invasion of bacterial pathogens. In addition to its antibiotic action, aeroplysinin-1 has been shown to display an anti-cancer effect [35,36]. Moreover, aeroplysinin-1 is a compound that interferes with key events in angiogenesis. As documented by Rodríguez-Nieto and co-workers, aeroplysinin-1 inhibited the growth and migration of endothelial cells as well as capillary tube formation on Matrigel at the low micromolar range [37]. Moreover, aeroplysinin-1 blocked extracellular matrix degradation via decrease in the MMP-2 and urokinase concentration. Finally, in vivo antiangiogenic effect of aeroplysinin-1 was confirmed by CAM and Matrigel plug assays [37]. Later, Martínez-Poveda and coworkers demonstrated that anti-angiogenic effects of aeroplysinin-1 may be associated either with selective induction of endothelial cells apoptosis or down-regulation of angiogenesis related genes such as TSP-1 and MCP-1 [38,39]. The extracellular signal-related kinases-mitogen-activated protein kinases (ERKMAPK) cascade and the PI3K/Akt pathway play a critical role in the controlling of both proliferation and survival transduction signals.

In a more recent study, the same group tested the potential of aeroplysinin-1 to inhibit a panel of protein kinase activities and the effects of aeroplysinin-1 treatment on Akt and Erk signaling pathways [40]. Aeroplysinin-1 was unable to produce a significant inhibitory effect on any of these protein kinase activities; however it caused an inhibition of both Akt and Erk phosphorylation in endothelial cells. This study supports the hypothesis proposing aeroplysinin-1 as transduction pathways modulator. Moreover, authors concluded that aeroplysinin-1 seems to have a specific effect on endothelial cells as a putative inhibitor of a specific unidentified mediator downstream of some endothelial tyrosine kinase receptor involved in the activation of both PI3K/Akt and MAPK pathways. 2.3. Fascaplysin Fascaplysin is a red pigment isolated from the Fijian sponge Fascaplysinopsis Bergquist sp. [41]. It exhibits an antiproliferative effect on cancer cells through induction of apoptosis via both mitochondrial and extrinsic pathways [42]. Although fascaplysin is known CDK4 inhibitor [43], recent study of Wang and co-workers showed that fascaplysin directly upregulates the expression of

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DR5/TRAIL, with subsequent activation of caspase-8 leading to mitochondrial dysfunction and apoptosis [44]. Moreover, fascaplysin also possesses antiangiogenic properties. The in vitro studies show that fascaplysin in low concentration provided selective inhibition of endothelial cells proliferation towards tumor cells and inhibit VEGF expression and secretion by cancer cells. Antiangiogenic potential of fascaplysin was also confirmed in in vivo assay [45]. In the following study of the same group, a sarcoma in vivo mice model was used to verify antiangiogenic effects of fascaplysin. The results of this study demonstrated that a variety of cell adhesion molecules (CAMs), such as Pecam (CD31), Glycam1, Vcam1 and CD2 are differentially expressed. These molecules affect the adhesive abilities of vascular cell and also tumor cell. The decrease of these CAMs and the down-regulated expression of endothelial cell markers-CD31 indicated that fascaplysin can inhibit the new vessel formation and thus can inhibit angiogenesis in tumor tissue [46]. The results showed that fascaplysin in endothelial cells induced G1 cell cycle arrest at micromolar range in a time-dependent manner. G1 cell cycle arrest was followed with increase in cells having sub-G0/G1 DNA content which is considered to be a marker of apoptotic cell death. Futhermore, an increase in the Bax/Bcl-2 ratio has indicated that apoptosis in HUVEC cells may involve a mitochondria pathway [47]. 2.4. Frondoside A Frondoside A is a triterpenoid glycoside isolated from the Atlantic cucumber, Cucumaria frondosa. At low concentrations it inhibits the growth and induced apoptosis of cancer cells via caspase activation [48,49]. In addition, Frondoside A also induced a time- and concentration-dependent inhibition of cell migration and invasion. Moreover, Frondoside A inhibited angiogenesis in vitro as well as in tumor xenografts in athymic mice. Furthermore, Frondoside A in nanomolar range also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay [50]. Collin et Adrian investigated the effect of Frondoside A on the ability of HUVEC cells to differentiate into capillary-like structures [51]. Frondoside A (1 mM) significantly abolished endothelial tube formation and was more than ten-fold more potent than the Suramin positive control in this assay. Frondoside A did not act through cytotoxicity (the HUVEC cells remained viable), however, the cells failed to form the tube-like structures seen in control. Induction of MMP is one of the essential steps of angiogenesis. It was found that frondoside A suppresses TPA-induced MMP-9 enzymatic activity, secretion and expression. This effect was associated with reduced activation of AP-1 and NF-kB, and subsequent induction of TIMP-1 and TIMP-2 expression [52]. 2.5. Philinopsides Philinopside A and philinopside E, saponin compounds isolated from the sea cucumber Pentacta quadrangularis, drew special interests, due to its both antiangiogenic and anticancer activity. The effects of philinopside A on angiogenesis was demonstrated by Tong and co-workers [53]. In a dose-dependent manner, philinopside A significantly inhibited the proliferation, migration and tube formation of human endothelial cells at micro – nanomolar range. Moreover, philinopside A inhibited angiogenesis in CAM assay. The angiogenesis inhibition could result from the suppression of angiogenesis-related receptor tyrosine kinases including VEGFR, FGFR, PDGFR and EGFR and their related signaling transduction. Philinopside E, similar to philinopside A, inhibited proliferation, migration, adhesion, tube-formation and induced apoptosis in both HMECs and HUVECs. Using CAM assay the antiangiogenic potential of philinopside E was also confirmed in in vivo conditions. The antiangiogenic mechanism of philinopside E is likely

associated with its interfering with the phosphorylation of VEGFR2, Akt, ERK, FAK and paxillin [54]. In addition, philinopside E was shown to interact with extracellular domain of kinase insert domain-containing receptor (KDR) to block its interaction with VEGF and the downstream signaling. Furthermore, philinopside E significantly suppressed integrin-driven downstream signaling followed by disruption of the actin cytoskeleton organization and decreased cell adhesion to vitronectin [55]. 2.6. Fucoidans Fucoidans represent a class of fucose-enriched sulphated polysaccharides of marine plant origin (different brown algae species). They affect many pathophysiological processes, such as inflammation, oxidative stress and carcinogenesis [56]. Although detailed molecular mechanism of anticancer effects is not fully understood, fucoidans can directly induce cytotoxicity and apoptosis in cancer cells. Fucoidans can also affect cancer cells indirectly e.g., as an antiangiogenic agent. They were shown to modulate angiogenesis but effect varied according to their molecular weight and sulfated degree. Low and middle molecular weight fucoidans (4–9 kDa and 15–20 kDa respectively) were found to stimulate angiogenesis [57,58]. Low molecular weight fucoidan was able to trigger the activation of the PI3K/AKT pathway, which plays a crucial role in angiogenesis and vasculogenesis [59]. On the other hand, natural fucoidan and oversulfated fucoidan inhibited angiogenesis [60]. Oversulphated fucoidan was found to potently inhibit the bFGF-induced HUVEC migration and tube formation by increasing the release of PAI-1 [61]. Koyanagi et al. demonstrated that fucoidan natural and oversulphated fucoidans significantly suppressed the proangiogenic actions of VEGF on HUVEC. The authors also found that oversulphated fucoidan suppressed the angiogenesis induced by Sarcoma 180 cells implanted in mice [60]. Furthermore, fucoidan in ex vivo assay suppressed angiogenesis in the aortic rings placed on Matrigel. Western blot and RT-PCR analyses indicated that fucoidan significantly reduced the expression of the VEGF-A [62]. Recently, it was shown that fucoidan decreases VEGF secretion in retinal pigment epithelium cells. Furthermore, fucoidan reduces VEGF-induced angiogenesis of peripheral endothelial cells [63]. A sulphated and acetylated fucoidan NDH01, extracted from seaweed Nemacystus decipiens, disrupted tube formation and inhibited the migration and cell growth of human microvascular endothelial cells. Moreover, NDH01 inhibited the phosphorylation of Smad/1/ 5/8, Erk and FAK. Besides, NDH01 blocked Smad1/5/8 signaling via interacting with bone morphogenetic protein 4 and downregulating bone morphogenetic protein 4 expressions [64]. In another study, Chen et al. [65] investigated whether low molecular weight fucoidan attenuates hypoxia-induced angiogenesis in bladder cancer cells. They concluded that under hypoxia conditions, the antiangiogenic activity of fucoidan in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway. Han et al. found that the activation of Akt signaling is involved in the induction of apoptosis and decreased angiogenesis of colon cancer cells treated with fucoidan [66]. Investigators concluded that fucoidan may serve as a potential therapeutic agent for colon cancer. 2.7. Fucoxanthin Fucoxanthin is a pigment that is widely distributed in brown algae such as Undaria pinnatifida [67]. When ingested, it is metabolized mainly to fucoxanthinol by digestive enzymes of the gastrointestinal tract. The anticancer effect of both substances is well documented (for review see [68]). Anti-proliferative and cancer preventing effects of fucoxanthin and fucoxanthinol are

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mediated through different signaling pathways, including the caspases, Bcl-2 proteins, MAPK, PI3K/Akt, JAK/STAT, AP-1, GADD45, and several other molecules [69]. However, besides direct effect on cancer cells, the in vitro/ex vivo investigations of fucoxanthin also revealed the antiangiogenic effect of this compound. fucoxanthin showed significant suppressive effect on the proliferation of HUVECs and tube formation. On the other hand, no significant activity on HUVECs chemotaxis was observed. In addition, fucoxanthin also suppressed microvessel growth rat aortic ring assay [70]. Furthermore, recent study showed that fucoxanthin suppressed the mRNA expression of FGF-2 and its receptor FGFR-1 with subsequent down-regulation of ERK1/2 and Akt phosphorylation [71]. Another study showed that cis isomers of fucoxanthins may suppress the NF-kB, JNK, and p38 signaling pathways in phorbol 12-myristate 13-acetate-induced MMP-2 and MMP-9 activity in human fibrosarcoma (HT1080) cells [72]. 2.8. Trabectedin Although this drug is not directly related to antiangiogenic agents, it is worth mentioning as a new approved treatment for soft tissue sarcomas known as Yondelis. Trabectedin is a tetrahydroisoquinoline alkaloid extracted from a Caribbean tunicate Ecteinascidia turbinate. It is believed that the marine-derived compound blocks the cell cycle at the G2/M phase by covalently binding to the minor DNA groove, altering DNA transcription and repair mechanism, but the actual mechanism is not yet precisely known. In a recent study, Atmaca et Uzunoglu [73] assessed the possible anti-angiogenic effects of trabectedin on HUVECs and breast cancer cell lines. Trabectedin suppressed the migration of both HUVECs and breast cancer cells. Angiogenic cytokines (protein expression was measured by Human Angiogenesis Antibody Array), such as GMCSF, IGFBP-2, VEGF, and uPA, were inhibited, while several antiangiogenic cytokines such as TIMP-1 and Serpin E1were induced in breast cancer cells [73]. Furthermore, the expression of VEGF mRNA was inhibited in all breast cancer cells lines [73]. Dossi et al. [74] investigated the mechanism of the antiangiogenic activity of trabectedin in myxoid liposarcomas. Trabectedin directly targeted endothelial cells, impairing functions relying on extracellular matrix remodeling through the upregulation of the inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 in vitro and in xenograft model (changes in both RNA and protein expressions). Moreover, trabectedin upregulated protein expression of the endogenous inhibitor thrombospondin-1 (it is considered a key regulator of angiogenesis-dependent dormancy in sarcoma) in vivo and in vitro [74]. 2.9. The clinical use of marine-derived agents against cancer Although anti-cancer effects of many marine-derived natural products have been evaluated in clinical trials, to date, only trabectedin (Yondelis1), cytarabine (Cytosar-U1), eribulin (Halaven1), the dolastatin 10 derivative, brentuximab vedotin (Adcetris1), and fludarabine (Fludara1) have been approved for use in clinical practice. Despite FDA approval, they are among 22 close chemical relatives still tested in clinical trials within anticancer research (Phases I–IV). Moreover, there are also 5 other marine-derived compounds in clinical trials focused on cancer therapy (Phases I–III) [2]. 2.9.1. Trabectedin Trabectedin belongs to intensively evaluated anticancer drugs in clinical research. Trabectedin has been registered by the EMA and recently also approved by the FDA for the treatment of patients

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with advanced soft-tissue sarcoma (STS). Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase II study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted. The aim of this study was to clarify the efficacy of trabectedin for extraskeletal myxoid chondrosarcoma (EMCS) or mesenchymal chondrosarcoma (MCS) patients. Objective response and progression-free survival were assessed in this study. This sub-analysis showed that trabectedin is effective for patients with EMCS and MCS compared with best supportive care subjects. Authors concluded that trabectedin becomes an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy [75]. Trabectedin as a relevant pleiotropic antitumoral agent is appropriate also for the treatment of soft tissue sarcomas (STS). It can be used in advanced STS, either after failure of anthracyclines and ifosfamide, especially when reaching a high-tumor control and a long-term benefit is a priority. Toxicity profile is acceptable and manageable with no reported cumulative toxicities [76]. Moreover, trabectedin has been found to be effective against other cancer types. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype (
2 previous responses to platinum). A total of 100 patients were treated with trabectedin in a dose of 1.3 mg/m2 i.v. every 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [singlenucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. Data prospectively confirmed that the signature of ‘repeated platinum sensitivity' identifies patients highly responsive to trabectedin. The results showed that the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum [77]. Moriceau et al. [78] reported a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life recurrent ovarian cancer patients. Authors found that trabectedin combined with pegylated liposomal doxorubicin seems efficient in and well tolerated by real-life recurrent ovarian cancer patients [78]. Due to the unique mechanism of action, trabectedin has the potential to act as antineoplastic agent also in several solid malignancies, including breast cancer [79,80]. The efficacy and safety of trabectedin in pretreated patients with triple-negative and HER2-overexpressing metastatic breast cancer (MBC) were evaluated in parallel-cohort phase II trial. Patients were treated with trabectedin at a dose of 1.3 mg/m2 i.v. every 3 weeks until progression or unmanageable/unacceptable toxicity. The study goals were to evaluate the efficacy using the objective response rate and also safety of the drug. Authors did not confirm responses of single-agent trabectedin in triple-negative MBC patients; however, it was well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Authors concluded that further studies are warranted to evaluate trabectedin in the combination with HER2-targeted treatments [79]. Another study took into consideration the data from preclinical and clinical research that demonstrated the linkage between xeroderma pigmentosum G gene (XPG) status and the trabectedin efficacy. This phase II study investigated the efficacy of trabectedin at a dose of 1.3 mg/m2 every 3 weeks in hormone receptor-positive, HER-2-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression. Trabectedin as single agent had limited activity in hormonepositive and HER-2-negative advanced breast cancer. The comparison of efficacy between high-XPG and low-XPG subjects showed no statistically significant differences.

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2.9.2. Cytarabine Another marine-derived compound cytarabine, which interfere with DNA synthesis, is mainly used in the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia (CML), and in the treatment and prevention of meningeal leukemia [81,82]. Recently, the European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves the outcome. In this clinical study (randomized, open-label, parallelgroup, phase III trial), the primary outcome was time to treatment failure from randomization to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II–IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomization. Results of this study showed that immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma [83]. Another study analyzed the correlation between different cytarabine regimens and outcome in 255 t(8;21) AML patients in China who received postremission consolidation chemotherapy only. The survival of AML patients treated with high-dose cytarabine (
2 g/m2) was superior to other dose levels in postremission consolidation chemotherapy. Moreover, patient survival was improved by 3–4 cycles of chemotherapy with an accumulated concentration of 36 g/m2 of cytarabine [84]. Thielen et al. [85] conducted a multicenter, randomized phase III trial with the aim to investigate whether the high-dose imatinib plus intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. The patients (n = 109) aged 18–65 years were randomly assigned into imatinib alone group (800 mg) or into group with imatinib (800 mg) in combination with two successive cycles of cytarabine (200 mg/m2) for 7 days. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Adverse events grades 3 and 4 were more common in the combination arm. Despite the results which showed that cytarabine did not improve the MMR rate in combination with imatinib, authors concluded that the study could be underpowered. 2.9.3. Eribulin Eribulin is a synthetic macrocyclic analog of the marine natural product halichondrin B, which is a potent naturally occurring mitotic inhibitor [86]. Eribulin was approved by the FDA against metastatic breast cancer and liposacoma. The purpose of recent Turkish study was to investigate the efficacy and safety of eribulin monotherapy in heavily pretreated MBC patients. This singlecenter, retrospective study enrolled sixty six MBC patients. Authors suggested that eribulin monotherapy is an effective and safe regimen for metastatic breast cancer patients with observed low toxicity profile compared to other intravenous cytotoxic agents [87]. Similar results with locally advanced or MBC patients demonstrated Korean multi-center, open-label, single-arm, phase IV clinical study [88]. Eribulin was administered at a dose of 1.4 mg/ m2 i.v. dose on days 1 and 8 of every 3 weeks. This study demonstrated the feasible safety profile and activity of eribulin in patients with MBC. Schoffski et al. [89] aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin mesilate (1.4 mg/m2 i.v. dose on days 1 and 8 of every 3 weeks) with that in patients who received dacarbazine as a control (doses of 850, 1000, or 1200 mg/m2 i.v. on days 1 every 3 weeks) in randomized, open-label, phase III clinical study. Investigators enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or

leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). The primary endpoint was overall survival in the intention-to-treat population. Authors summarized that overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma [89]. 2.9.4. Brentuximab vedotin The recent addition to the arsenal of approved antineoplastic marine-derived agents is brentuximab vedotin, a chimeric antibody attached through a protease-cleavable linker to a derivative of the potent antitubulin agent dolastatin 10 [90]. FDA approved this agent for the use against Hodgkin's lymphoma and anaplastic large cell lymphoma [91,92]. Chen et al. published 5-year results from the pivotal phase II trial of brentuximab vedotin in patients (n = 102) with relapsed/refractory Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. Patients who achieved a complete response to brentuximab vedotin (n = 34) had estimated overall survival and progression-free survival rates of 64% and 52%, respectively. Authors concluded that a subset of patients with relapsed/refractory HL who obtained complete response with single-agent brentuximab vedotin achieved longterm disease control and may potentially be cured [93]. Another, single-center observational study, was conducted with the aim to evaluate the long-term effectiveness of brentuximab vedotin in HL and systemic anaplastic large cell lymphoma (sALCL) patients. The best response rate in the treated 53 patients (43 HL and 10 sALCL) was 69.8% (46.5% CR) in HL and 100% (80% CR) for sALCL, respectively. With a median patient follow-up of 36.8 months, the estimated median duration of response was 31.5 months for HL and 17.8 for sALCL, respectively. Results demonstrated that 51% of patients treated with brentuximab vedotin can be regarded as “long-term responders”. In addition, in all patients who underwent stem cell transplantation immediately after brentuximab vedotin treatment, the procedure was consolidative. Moreover, patients who have remained in continuous complete response without any consolidation after therapy, brentuximab vedotin can cause prolonged disease control [94]. 2.9.5. Fludarabine A fluorinated analog of vidarabine is fludarabine. Fludarabine as a purine analog is highly effective in the treatment of chronic lymphocytic leukemia (CLL) [95]. Currently, the fludarabine is clinically used mainly in combining regimens [96–98]. In the multicenter, open-label, phase III study, patients with relapsed CLL were randomized to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC, n = 183) or FC alone (n = 182) the primary endpoint was the progression-free survival (PFS). Results demonstrated that OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL [96]. Moreover, fludarabine have shown promising outcomes in relapsed or refractory AML. The effects of fludarabine and cytarabine consolidation therapy for t(8;21) AML patients were evaluated in a prospective randomized study. Subjects with t(8;21) AML after achieving complete remission were randomly assigned to receive four course consolidation with fludarabine (n = 23) or cytarabine (n = 22). Overall survival of both groups at 36 months was 100% and 51.4%, respectively (P = 0.004), suggesting a benefit of consolidation therapy with fludarabine for t(8;21) AML patients, especially, those without c-kit mutations [98]. Recently, Guolo et al. [99] analyzed 105 consecutive AML patients treated with the same induction-consolidation program between years 2004 and 2013. The first induction course included fludarabine and high-

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dose cytarabine plus idarubicin, with or without gemtuzumabozogamicin. Authors concluded that fludarabine/cytarabine plus idarubicin double induction followed by risk-oriented consolidation therapy can result in good overall outcome [99]. This therapy was generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30day mortality of 4.8% [99]. 3. New potential therapeutic targets for angiogenesis – galectins and microRNAs Ongoing research has demonstrated that galectins contribute to proper endothelial cell function during tumor angiogenesis. Similarly, microRNAs have been documented to play an important role in diverse biological processes, including signaling in endothelial cell tube formation. From this reasons, galectins and microRNAs seem to be potentially interesting therapeutic targets for cancer angiogenesis. 3.1. Galectins Galectins belong to a family of carbohydrate-binding proteins with an affinity for b-galactosides. They show a high level of evolutionary conservation, having been identified in many species from nematodes to mammals, with 15 mammalian galectins identified to date. Endothelial cells were found to express four family members, i.e. galectin-1, galectin-3, galectin-8, and galectin-9 [100]. Fig. 1 shows the key processes of angiogenesis influenced by galectins. Low mRNA levels of galectin-2, -4, and -12 have also been detected in cultured endothelial cells but expression at the protein level is still unresolved [101–103]. Galectin-targeted angiostatic therapy can be aimed at scavenging the secreted angiostimulatory galectins with antibodies – comparable to e.g. the anti-VEGF antibody bevacizumab – or it can aim to block the function of galectins on endothelial cells by interfering with carbohydrate binding [104]. Galectin-1 is up-regulated in the endothelium of tumors of different origin and has been shown to be the target for anginex [105,106]. The targeting of galectin-1 and antagonizing of its function directly result in attenuation of tumor angiogenesis in vitro and in vivo. In addition, Dings et al. showed that antiangiogenic agent anginex can enhance the radiation response what may lead to improved clinical outcome in treating cancer patients [107]. In addition, anginex can affect endothelial cell anergy and allow a normal immune response in tumors [108]. The same research group also reported on 6DBF7, a dibenzofuran (DBF)-based peptidomimetic of the gal-1 antagonist anginex and 6DBF7 shows improved in vitro and in vivo activity profiles over parent anginex [109]. Additionally, they designed and tested DBF analogs – DB21 and DB16. Using tumor mouse models (B16F10 melanoma, LS174 lung, and MA148 ovarian), they found that DB21 inhibits tumor angiogenesis and tumor growth significantly better than 6DBF7, DB16, or anginex [110]. While the advantage of the former relies on the specificity of monoclonal antibodies for

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individual galectins, the advantage of the latter approach is that multivalent inhibitors could be developed that simultaneously block the function of multiple endothelial galectins [104]. Several other compounds have been developed that interfere with galectin function in tumor angiogenesis. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylationdependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment [111]. Rabinovich et al. summarized that low molecular weight synthetic lactulose amines may be potentially used to specifically block different steps of tumor growth and angiogenesis [112]. Galectin-3C, N-terminally truncated form of galectin-3, was efficacious in a xenograft mouse model of human multiple myeloma, moreover it enhanced the anti-tumor activity of bortezomib in vitro and in vivo [113]. Authors concluded that these data provide the rationale for continued evaluation of galectin-3C in clinical trials for the treatment of multiple myeloma. Moreover, multiple triggers have been found to influence endothelial expression, including hypoxia, cytokines, and cell–cell interactions [104]. In this regard, a better insight in these signaling/ regulatory pathways will help to elucidate the modulation of endothelial galectin expression during tumor angiogenesis with the potential benefits for cancer treatment in humans [114]. 3.2. microRNAs Over the last few years, novel therapeutic approach for the treatment of cancer has been proposed: microRNAs (miRs). miRs constitute of family of conserved non-coding small RNAs, which repress gene expression post-transcriptionally by targeting 30 untranslated regions (30 UTRs) of mRNAs [115] and play a key role in diverse biological processes such as development, differentiation, cell proliferation, and apoptosis. Mounting evidence indicates they are also highly relevant to disease processes, such as cancer [24– 26]. It makes miRs an attractive prospect for new gene-based therapies. In general, there are two approaches to developing miRbased therapeutics: mimics of anti-angiomiRs, or antagomirs of proangiomiRs [116]. According to publicly available information, a strong anti-angiomiRs candidate for future tumor angiogenesis treatment is miR-126, the most abundant microRNA in endothelial cells. In in vivo models, loss of miR-126 impaired endothelial cell migration during vessel growth as well as collapsed vessel lumens and a compromised endothelial tube organization which is mainly due to up-regulation of the miR-126 targets Sprouty Related EVH Domain containing protein 1 (SPRED-1) and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta), which are both negative regulators of the VEGF/VEGFR signaling pathway [117– 119]. miR-126 also enhanced Angiopoietin-1 (Ang-1) signaling, implicating that miR-126 is also involved in vessel stabilization and maturation [120]. These data suggest that miR-126 functions as a regulator of endothelial homeostasis (Fig. 2). In contrast, in several studies miR-126 was reported to act as a tumor suppressor and was shown to be downregulated in various cancer types including

Fig. 1. The role of galectins (-1, -3, -8, -9) in angiogenesis. Both gal-1 and gal-3 stimulate multiple endothelial functions during angiogenesis, gal-8 regulate migration and vascular tube formation, and gal-9D5 influence the activation and proliferation of endothelial cells. EC, endothelial cells; BM, basement membrane; P, pericytes; gal-1, galectin-1; gal-3, galectin-3; gal-8, galectin-8; gal-9D5, splice variant galectin-9 lacking exon 5.

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in initial endothelial cell activation and also contribute to the subsequent steps of the angiogenesis cascade. Therefore, one of the major challenges for clinical oncologists in targeting galectins is the translation of current knowledge into the design and development of effective galectin inhibitors in cancer therapy. Emerging evidence suggests that targeting microRNAs offer an alternative treatment of uncharacteristic angiogenesis in humans. The potential challenges for angiomicroRNAs therapeutics as angiomodulators in cancer therapy include the efficiency of the delivery system, avoiding off target effects, and optimizing the dose. Conflict of interest All authors declare no conflict of interest. Fig. 2. miR-126 as a regulator of endothelial homeostasis. The decrease in miR-126 levels causes SPRED-1 and PI3KR2 up-regulation and Ang1 down-regulation thereby blocking VEGF/VEGFR signaling and consequently angiogenesis.

breast, gastric, prostate cancer and RCC [121]. This underscores the critical importance of cell/tissue-specific miRNA targeting [122]. Besides miR-126, an example of classic angiomiR is miR-132, which enhances growth factor signaling by targeting the negative regulator of Ras, p120RasGAP [123] and PTEN [124]. miRNAs expression may be regulated by ischemia, also referred as hypoxamiRs. An example of a hypoxamiR is miR-210, and its expression is induced by hypoxic conditions in a hypoxia inducible factor-1 (HIF-1) dependent manner. In endothelial cells, miR-210 targets ephrin-A3, thereby modulating the angiogenic response to hypoxia [125]. Moreover, this miR inhibits caspase activity and prevents cell apoptosis [126]. Herein we have mentioned some representative angiomiRs, but several research groups have reviewed the many different miRs that are involved in angiogenesis [26,127,128]. However, there are certain limitations to therapeutic targeting that must be considered. For example, the same miRNA (e.g. miR-126) can exert the opposite biological effect depending on cellular context, therefore tissue-specific delivery approaches should be considered in the development of new miRNA-based therapeutic strategies [129]. The discovery of miRNAs allowed the controlling of gene expression and thus gave the possibility for clinical validation of prognostic and diagnostic miRNA panels. Using large cohort studies it would enable introduction into clinical practice. An effort to identify major miRNA targets and developing the safe and specific methods of delivery of miRNA-based treatments could allow modulation of miRNAs to become a basis for the management of tumor angiogenesis in humans [130]. 4. Conclusions Marine natural products have been shown to suppress angiogenesis or to disrupt established blood vessels. Evidence is accumulating to show that marine-derived antiangiogenic protein kinase modulators is a therapeutic avenue in tumor angiogenesis. The more precise evaluation of the structure-effect relationships of marine-derived natural products to analyze the relationships between their antiangiogenic mechanisms and their cytotoxicity on cancer cells and between their primary targets and their antiangiogenic mechanisms are important questions for clinical research. The elucidation of these relationships could generate new therapeutical approaches in cancer disease. Ongoing research has shown that galectin-1 and galectin-3 and most likely also galectin-8 and galectin-9, contribute to proper endothelial cell function during tumor angiogenesis. These galectins are involved

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