Role of coenzymes in cancer metabolism

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Review

Role of coenzymes in cancer metabolism Maheshwor Thapaa,b, Guido Dallmanna, a b

⁎

Department of Research and Development, Biocrates Life Science Ag, Innsbruck, Austria Paracelsus Medical University, Salzburg, Austria

A R T I C LE I N FO

A B S T R A C T

Keywords: Coenzymes Mitochondria Cancer

Cancer is a heterogeneous set of diseases characterized by the rewiring of cellular signaling and the reprogramming of metabolic pathways to sustain growth and proliferation. In past decades, studies were focused primarily on the genetic complexity of cancer. Recently, increasing number of studies have discovered several mutations among metabolic enzymes in different tumor cells. Most of the enzymes are regulated by coenzymes, organic cofactors, that function as intermediate carrier of electrons or functional groups that are transferred during the reaction. However, the precise role of cofactors is not well elucidated. In this review, we discuss several metabolic enzymes associated to cancer metabolism rewiring, whose inhibition may represent a therapeutic target. Such enzymes, upon expression or inhibition, may impact also the coenzymes levels, but only in few cases, it was possible to direct correlate coenzymes changes with a specific enzyme. In addition, we also summarize an up-to-date information on biological role of some coenzymes, preclinical and clinical studies, that have been carried out in various cancers and their outputs.

1. Introduction Mitochondria are central organelles for energy metabolism and adenosine triphosphate (ATP) synthesis. Besides fulfilling energy demands, mitochondria play a major role in calcium homeostasis [1], programmed cell death [2], reactive oxygen species (ROS) generation, and oxidative stress [3]. The tricarboxylic acid (TCA) cycle within mitochondria is vital for the cellular metabolism that generates nicotinamide adenine dinucleotide reduced (NADH) and flavin adenine dinucleotide reduced (FADH2). NADH and FADH2 are primary cofactors for transferring electrons to the electron transport chain (ETC) that carries out cellular respiration (Fig. 1). Moreover, many TCA cycle intermediates undergo different anabolic pathways for production of nucleic acids, lipids, and proteins. Thus, dysfunction of mitochondria

components will directly affect a wide range of anabolic and catabolic pathways resulting in varieties of abnormalities [4] The majority of neurodegenerative diseases are characterized by mitochondrial dysfunction and oxidative stress [5,6]. Cardiovascular disorders are related to improper mitochondrial homeostasis [7]. All these factors bring mitochondria as an emerging drug target for various disease conditions such as cardiovascular disorders [7,8] neurodegenerative diseases [3,5], and cancers [2] Cellular metabolism refers to the sequences of controlled biochemical reactions in a living organism which when altered leads to cell transformation. The altered cells will adapt themselves to metabolic changes and form the basis for tumor initiation and cancer progression. Cancer progression is characterized by genomic instability and mutation due to the rewiring of cellular signaling, deregulating of cellular

Abbreviations: ATP, adenosine triphosphate; TCA, tricarboxylic acid cycle; NADH, nicotinamide adenine dinucleotide reduced; FADH2, flavin adenine dinucleotide reduced; ETC, electron transport chain; PPP, pentose phosphate pathway; PDC, pyruvate dehydrogenase complex; CoA, coenzyme A; TPP, thiamine pyrophosphate; FAD, flavin adenine dinucleotide; NAD+, nicotinamide adenine dinucleotide; HIF, hypoxia inducible factor; FH, fumarate hydratase; SDH, succinate dehydrogenase; ADP, adenosine diphosphate; LDH-A, lactate dehydrogenase A; FAO, fatty acid oxidation; ROS, reactive oxygen species; SOG pathway, the serine one-carbon cycle glycine synthesis pathway; NSCLC, non-small-cell lung cancer; AMPK, AMP-activated protein kinase; G6PD, Glucose-6-phosphate dehydrogenase; IDH, isocitrate dehydrogenase; ME, malic enzyme; ALDH, aldehyde dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; ATC, anaplastic thyroid carcinoma; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; CRC, colorectal cancer; NAM, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; NAMPT, nicotinamide phosphoribosyl transferase; ATO, arsenic trioxide; NNT, nicotinamide nucleotide transhydrogenase; α-LA, alfa-lipoic acid; DHLA, dihydrolipoic acid; MMP, matrix metalloproteinase; ERK, signal-regulated kinase; CoQ10, Coenzyme Q10; UbQ, ubiquinone; Ndufc2, NADH dehydrogenase ubiquinone 1 subunit; αTOS, α-tocopheryl succinate; FABP3, fatty acid binding protein 3; EGFR-Grb2, epidermal growth factor receptor and growth factor receptor-bound protein 2; mTOR, mammalian target of rifampicin ⁎ Corresponding author at: Research and development department, Biocrates Life Science AG, Eduard-Bodem-Gasse 8, 6020, Innsbruck, Austria. E-mail address: [email protected] (G. Dallmann). https://doi.org/10.1016/j.semcdb.2019.05.027 Received 25 March 2019; Received in revised form 27 May 2019; Accepted 28 May 2019 1084-9521/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Please cite this article as: Maheshwor Thapa and Guido Dallmann, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.05.027

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Fig. 1. Overview of coenzymes in different metabolic pathway.

enzymes (FH, SDH, IDH) in cancer development [30]. Considering all available facts, it is likely that change in coenzyme level may directly impact enzyme activity and hence affect different biochemical reactions. Thus, studies on coenzyme activity provides better insight into understanding the roles of enzymes in different metabolic processes including cancer. In this review, we aim to summarize the biological role of the most important coenzymes that have been tried in cancer treatment, preclinical and clinical, and their outcomes. Also, we aim to gather up-to-date progress concerning the association of coenzymes with cancer initiation and progression.

energetics, and reprogramming of metabolism needed to satisfy the altered bioenergetic requirements [9]. The most prominent pathway relating to cancer cell proliferation is aerobic glycolysis [10]. Otto Warburg, in 1956, described the tendency of cancer cells to rely on glycolytic metabolism and produce lactate in presence of oxygen, indicating defects in mitochondrial respiration for the basis of cancer proliferation [11]. The “Warburg effect” is widely observed in clinical settings for tumor imaging by 2–18 F fluoro-2deoxy-D-glucose (18 F-FDG) positron emission tomography [12]. However, recent studies suggest that the malignant transformation not only involve aerobic glycolysis but also involve increased flux from lipid biosynthesis and metabolism [13,14], the pentose phosphate pathway (PPP) [15], and high glutamine consumption. Most of the cancer cells in these studies showed high glucose intake but reduced glucose oxidation in TCA cycle. The glucose consumed by cancer cells is then diverted for use in different anabolic processes that include ribose production, amino acid synthesis, and protein glycosylation [16,17] Different metabolic reactions are regulated by different enzymes. Targeting key metabolic enzymes improves therapeutic efficacy by inhibiting enzyme activity and promoting drug-induced apoptosis of cancer cells [18]. Most enzyme activities are regulated by coenzymes, organic molecules that bind to the active sites of enzymes to catalyze a reaction. Without coenzymes, enzymes cannot function properly [19]. Coenzymes function as intermediate carriers of electrons or functional groups that are transferred during a reaction. For example, the pyruvate dehydrogenase complex (PDC) requires several coenzymes, free coenzyme (CoA), thiamine pyrophosphate (TPP), lipoic acid (LA), flavin adenine dinucleotide (FAD), and NAD+/NADH ratio in order to convert pyruvate to acetyl-CoA (Fig. 1) [20]. Many reaction pathways are directly affected by the levels of two specific coenzymes NAD(H) and NADP(H) [21]. Inside mitochondria, mutations in complex I (CI) [22,23], fumarate hydratase (FH) [24], succinate dehydrogenase (SDH) [25,26] and complex III (CIII) are the common events of cancer cells [27] which are regulated by coenzymes, NADH/NAD+, FADH2/FAD, and CoQ/CoQH2 (Fig. 1). These alterations in cancer cells promote glutamine utilization as an alternative pathway to adapt to their altered metabolism. FH, SDH and isocitrate dehydrogenase (IDH) are de facto tumor suppressor genes whose mutations cause oncogenic hits to trigger cellular transformation and facilitate tumor growth and adaptation via stabilization of hypoxia inducible factor-1α (HIF-1α) [28,29]. Recently published review article summarized the role of oncometabolites (succinate, fumarate and 2-hydroxyglutarate) and their related

2. Important coenzymes 2.1. Adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ATP is an important cofactor for storing and transferring energy in cells [31]. Most differentiated cells undergo glucose metabolism by oxidation of pyruvate in mitochondrial TCA cycle. Coenzymes like NADH and FADH2 are products that feed oxidative phosphorylation for ATP production and cellular respiration. These cells metabolize glucose to lactic acid only in absence of oxygen. In contrast, the tumor cells convert glucose to lactate even in presence of oxygen which is referred to as aerobic glycolysis [32]. Lactate dehydrogenase A (LDH-A) catalyzes the conversion of pyruvate to lactate in exchange for NADH to NAD+ which maintains the tumor micro-environment for survival and proliferation (Fig. 1). The mechanism behind this metabolic shift to glycolytic metabolism is not clearly understood but recent works suggest that HIF expression may contribute to Warburg’s effect by diminishing pyruvate dehydrogenase activity and inducing fermentative glycolysis [33]. Xie et al. [34] clearly showed HIF-1α stabilization and increased LDH-A expression in von hippel lindau (VHL) and FH deficient kidney tumors. In addition, they used FH/LDH-A deficient cells to suppress both TCA cycle and fermentative glycolysis, and observed 50–60% reduction of intracellular ATP [34]. ATP production is downregulated by glycolytic inhibitors such as WZB117 in lung and breast cancer [35] and 3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid (FX11) in lymphoma and pancreatic cancer xenografts [36]. This decreased ATP production promotes drug sensitivity by drug accumulation inside cells. However, the molecular mechanism of improving drug resistance by targeting metabolism is not fully understood [18]. 2

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were performed on 15 patients with stage IIIB or stage IV NSCLC [53,54]. The result showed that ATP at 50 μm/kg/minute and route of administration had no effect on NSCLC [54]. Although, the result was not promising, phase III clinical trials were conducted with 58 NSCLC patients. Finally, the author concluded that single therapy of ATP did not lead to tumor regression but did prolong survival in weight-losing NSCLC patients of stage IIIB [55]. Another randomized clinical trial was conducted with 58 NSCLC patients. 28 NSCLC patients were treated with intravenous infusion of ATP. The study reported the beneficial effects of ATP on muscle strength, weight and quality of life of advanced NSCLC over the 6-month period of investigation [56]. Beijer et al. studied the feasibility of ATP infusion in home care settings and the effect of ATP on functional status and quality of life in preterminal patients. 100 patients with different types of pre-terminal cancer (colon cancer, breast cancer, lung cancer, and other types of cancer) were involved in the trial were divided randomly into 2 groups, intervention group were provided with palliative care, dietetic advice, and regular ATP infusion over a period of 8 weeks and the control group with palliative care, dietetic advice, but no ATP. The majority, 63%, were without side effects. The author concluded that ATP at a maximum dose of 50 μg/kg/min can be safely administered in home care settings [57,58] In addition, Beijer et al. studied the effects of ATP infusions on nutritional status and survival of different cancer types. They found the increase in survival in preterminal cancer, especially in weight stable patients and patients with lung cancer [59]. However, large studies were warranted to define the effect of ATP in different and specific cancer types. Further, they continued to investigate the effect of ATP on the quality of life, functional status, and fatigue in preterminal cancer patients. Large majority of outcome parameters investigated were not statistically significant between ATP and control group. In fact, most of the parameters were found stable or even improved over time in control group. The author concluded that with the dose and schedule studied, ATP infusions did not significantly impact on quality of life, functional status, and fatigue in different preterminal cancer patients, However, the author suggest the need of further investigations on the dose of ATP, duration, and frequency of ATP treatment [60]. The role of ATP in drug resistance has been discussed widely. Increased ATP levels activate ATP-binding cassette transporters which leads to increased drug efflux and upregulate HIF-α signal. This upregulated HIF induced hypoxia is associated with drug resistance [18]. Cells that undergo aerobic respiration have high ATP/ADP and NADH/ NAD+ ratios. Change in the ATP/ADP ratio may impact cell growth. When the ATP level is decreased, adenylate kinases gets activated converting 2 molecules of ADP to ATP and AMP maintaining viable ATP/ADP ratio [32,61]. This increases the accumulation of AMP. When AMP/ADP or ADP/ATP ratio is increased in cell, AMP-activated protein kinase (AMPK) is activated. AMPK activation exerts a cytostatic effect which could be the possible mechanism of some cancer suppressor proteins like liver kinase B1. Further, cell cycle process is down regulated with activation of AMPK [62]. Metformin and Phenformin activate AMPK in cells which suggests that these agents can be used for cancer therapy [32]. Treatment of cultured human astrocytoma cells with 100 μm ATP resulted in significant reduction in cell numbers [63].

More recently, studies in cancer research demonstrate that mitochondrial function is not impaired in most cancer cell, suggesting an alternative explanation for aerobic glycolysis in cancer cells [32]. Fatty acid oxidation (FAO) generates large amounts of ATP especially in the cells with high energy demand like cardiomyocytes [37]. Metabolic stress in cancer cells will be minimized by FAO derived ATP and NADPH, thereby balancing ROS and supplying the high energy demand needed for its growth and survival [38]. NADPH reduces glutathione from its oxidized (glutathione disulfide, GSSG) to reduced (glutathione, GSH) form and protects cells against oxidative stress by ROS [38]. In addition, serine, folate, and glycine metabolism provide ATP, NADPH, and purine required for cancer cell growth and proliferation via the serine, one-carbon cycle, glycine synthesis (SOG) pathway [39]. The SOG pathway was proved as a novel pathway for ATP generation in murine model of Myc-driven liver tumorigenesis [40]. In vitro study for treatment of acute lymphocytic leukemia have shown strong association of methotrexate sensitivity and expression of SOG pathway mitochondrial enzymes [41]. The SOG pathway in cancer cells was inhibited by antifolate drug methotrexate. The result showed significant inhibition of ATP production by low ATP levels, inhibition of NADPH by reduced fatty acid synthesis from glucose, inhibition of purine synthesis by low adenine nucleotide levels and reduced ribonucleotide synthesis from glucose [39]. Previous studies have shown the beneficial effect of ATP in tumor growth and progression in various cancers. Extracellular ATP was found to inhibit cell growth, cause cell cycle arrest, and induce apoptosis in TE-13 human squamous esophageal carcinoma cells in vitro [42] Similar results have been obtained by Maaser et al. with clear cell cycle arrest and apoptosis by ATP in human esophageal carcinoma cells [43]. Daily intraperitoneal injections of ATP (25 mM) have effectively reduced the growth of advanced hormone-refractory prostate carcinoma tumors with no adverse effect on host mice [44]. In vitro, ex vivo and in vivo experiments conducted by Qian et al. strongly suggest the intake of extracellular ATP by human lung cancer cells and tumors to supplement their extra energy needs for their growth, proliferation, and survival. Non-hydrolyzable fluorescent ATP (NHF-ATP), as a surrogate ATP, at 10 μmol/L was fed to human non-small-cell lung cancer (NSCLC) cells as well as nontumorigenic lung cells. Compared with nontumorigenic lung cells, extracellular ATP internalization was drastically enhanced in NSCLC cells. Thus, during the temporary shortage of intracellular ATP, cancer cells quickly take up extracellular ATP to meet their metabolic and growth needs [45]. Inconsistent results have been obtained regarding the role of ATP in cancer. Some studies showed that ATP stimulates the growth of human cancer cells such as Coca-2 colon cancer cells [46] and A549 human lung cancer cells [47] whereas other studies demonstrated the inhibition of Caco-2 [48] and glioblastoma [49] cells proliferation. Zhang et al. extensively studied the effect of extracellular ATP in various cancer cells. Extracellular ATP promotes in vitro invasion of prostate cancer cells by activating Rho GTPase Rac1and Cdc42 and expression of MMPs [50]. Furthermore, Zhang et al. showed that ATP inhibits the proliferation of MCF-7 and MDA-MB-231 breast cancer cells, but it promotes the invasion and metastasis of breast cancer via P2Y2-β-catenin axis suggesting the possibility of blocking of P2Y2-βcatenin axis as a potential target for breast cancer [51]. This suggest that the use of ATP in cancer treatment might have a risk in promoting metastasis of breast and prostate cancer cells. Dixon et al. investigated the functional effect of ATP on breast tumor cell lines. High doses of ATP and analogue of ATP (ATPγS) both showed decreased growth of MCF-7 cells whereas ADP was found partially effective [52]. Few clinical trials have been conducted to investigate the efficacy of ATP. A phase I clinical trial was carried out with intravenous administration of ATP in a dose ranging from 50 to 100 μm/kg/minute to 14 men suffering from NSCLC. ATP at dose 50 μm/kg/minute was found as the safely tolerated dose and an appropriate dose for Phase II trial in patients with advanced cancer [53]. Based on the result from phase I clinical trial, phase II clinical trials

2.2. Nicotinamide adenine dinucleotide phosphate reduced (NADPH)/ Nicotinamide adenine dinucleotide phosphate (NADP) NADPH, a major cofactor, works as an electron carrier to maintain redox homeostasis, regulate reductive biosynthesis, and signal transduction [64]. NADPH is primarily produced either by PPP, catalyzed by Glucose-6-phosphate dehydrogenase (G6PD) to make nucleotide building block ribose or by the 10-formyl-THF pathway for purine synthesis [65]. Recently, NADP+ specific forms of IDH (IDH1), malic enzyme (ME), aldehyde dehydrogenase (ALDH), as well as NAD-kinase (NADK) were identified as significant contributors for NADPH regeneration (Fig. 1) [64] It has been reported that in order to maintain 3

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causes HIF-1α destabilization triggering pseudonormoxia [23,82] NAD+ synthesis, a major salvage pathway, involves the conversion of nicotinamide adenine dinucleotide (NAM) to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyl transferase (NAMPT). NMN adenyltransferase further converts NMN to NAD+ (Fig. 1). NAD+ is a major coenzyme in many biological reactions as well as substrate for NAD+ converting enzymes such as cADP-ribose synthases (CD38 and CD157), poly-ADP-ribose polymerases, and sirtuins. Thus, by controlling synthesis of NAD+, NAMPT regulates the activity of these enzymes [83]. Compared to normal cells, tumor cells have high NAD+ turnover rate which makes NAMPT an attractive therapeutic target for cancer. Reports have shown the overexpression of NAMPT in several tumors including ovarian, breast, prostate, colorectal, gastric, endometrial carcinomas, melanoma, and gliomas [84–86]. Conversely, its downregulation suppresses tumor cell growth in vitro and in vivo and sensitizes cells to oxidative damage. NAMPT inhibition causes depletion of NAD+ resulting in attenuation of tumor growth and induction of apoptosis [87,88]. The inhibition of elevated NAMPT expression in prostate cancer cells confirmed suppressed growth and invasion in vitro and growth of tumor xenografts in vivo [85]. Many clinical and non-clinical studies have been performed to inhibit NAMPT expression. Tiazofurin and Selenazofurin incubated with L1210 cells resulted in interference with NAD synthesis, low cellular NAD content, and inhibition of cell growth. These antineoplastic effects were observed by their respective intracellular active metabolic form which are structural analogs of NAD. However, these NAD analogs affect cellular energy metabolism causing general cytotoxicity [89]. GMX1778 (also called CHS-828) and AP0866 (also called FK866/ WK175) are potent small molecules that inhibit NAMPT expression and are already under different phases of clinical trials [90]. Each compound showed strong antitumor activities both in vivo and in vitro in different tumor types like renal cell carcinoma xenograft model [91], human liver carcinoma cells [87], prostate cancer cell [85], oral squamous cell carcinoma [92], neuroendocrine tumors (midgut carcinoid, pancreatic carcinoid, and medullary thyroid carcinoma) [93] lymphoma cell [94], and human myeloma cell [95]. FK866 inhibits NAMPT activity, reduces NAD and ATP levels, and induces apoptosis in p53 deficient hepatocarcinoma cells suggesting that FK866-mediated cell death is independent of functional p53 [96]. Further, FK866-induced NAMPT inhibition led to activation of AMPK and inhibition of mammalian target of rifampicin (mTOR) signaling pathway which strongly suggest the use of FK866 to reduce cancer cell growth [96]. Another study demonstrates that FK866 reduces cellular NAD levels in estrogen receptor-positive breast cancer cells, upregulates p53 activity, induce p21 and Bcl-2-associated X protein expression, and induces cell death [97]. GMX1778 decreases the NAD levels and increases the intracellular ROS in cancer cells by increasing superoxide levels while not inducing ROS in normal cells [98]. Recently, arsenic trioxide (ATO) was proved as a chemotherapy agent to decrease levels of NAMPT proteins and suppress cell growth in oral squamous cell carcinoma. However, the combined regimen of ATO and KF866 showed synergistic cytotoxicity even at very low concentration of ATO [92]. Nicotinamide nucleotide transhydrogenase (NNT), in the inner mitochondrial membrane, catalyzes the transfers of reducing equivalents from NADH to NADPH playing a crucial role in regulating cellular energy metabolism and redox status [99]. Shifting the NADH/NAD+ ratio affect glucose and glutamine metabolism in TCA cycle. It was observed that knockdown of NNT activates glucose catabolism and inhibits glutamine metabolism in MkMe15 melanoma cells. The increase in glucose catabolism is partially through activation of pyruvate carboxylase in response to a lower NADH/NAD+ ratio [100,101]. The cellular NADPH/NADP+ ratio was found decreased in NNT knockeddown cells, whereas the ratio was higher in NNT over-expressing cells [99,100]. All these evidences have raised the importance of coenzymes in coordinating glucose and glutamine utilization in tumor cells.

the abnormal demand of proliferation in cancer, PPP is overexpressed in many cancers such as liver cancer, colorectal cancer, leukemia, and lung cancer [66–68]. A recent review article has summarized the G6PD overexpression in different tumors [66]. G6PD overexpression generates high levels of NADPH, an essential molecule needed for biosynthesis of fatty acids and cholesterol, that scavenge ROS produced during rapid proliferation of cancer cells. However, the PPP depends on the availability of glucose. At low glucose level, the PPP is down regulated generating lower levels of NADPH. Low NADPH levels may increase ROS levels initiating oxidative damage and cell death, but under these conditions cancer cells undergo alternative mechanism to generate NADPH by ME and IDH1 to sustain growth and proliferation (Fig. 1) [69,70]. The last reaction in PPP, catalyzed by 6-phosphogluconate dehydrogenase (6PGD), yields a second NADPH. Many studies have been carried out to study the role and therapeutic value of 6PGD activity in tumor growth and metabolism. 6PGD expression was found upregulated and activated in cervical cancer cells and patient tissues [71], anaplastic thyroid carcinoma (ATC) [72], breast cancer [73], and lung cancer [74] with its inhibition significantly reducing growth, migration, and survival. 6PGD inhibition further sensitizes cervical cancer and breast cancer to chemotherapeutic agents in vitro via activation of AMPK [71,73]. One of the mechanisms of chemotherapeutic drugs is to produce ROS and create oxidative damage to cancer cells. However, in response to ROS accumulation, cancer cells activate PPP producing high levels of NADPH and ATP that counteracts oxidative damage. This could be one of the major factor for drug resistance [70,18]. Several cancers, including lung cancer and ATC, are found to be resistant to chemotherapy. A recent work on cisplatin-induced resistant lung cancer cells revealed distinct metabolic profile of PPP and redox molecules compared to its normal counterparts. G6PD inhibition has successfully restored the drug sensitivity on those cisplatin resistant cells [75] Furthermore, inhibiting 6PGD significantly sensitizes ATC cells’ response to doxorubicin treatment [72]. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), an NAD(P) dependent enzyme, plays a major role in one carbon metabolism. Studies have shown that MTHFD2 is overexpressed in rapidly proliferating malignant tumors and generates NADPH for protection from ROS [76,77]. MTHFD2 is the most overexpressed NADPH generating enzyme in colorectal cancer (CRC) and inhibition of MTHFD2 with LY345899 showed potent antitumor activity in vivo suggesting LY345899 as a promising therapeutic compound for CRC treatment [78]. Under hypoxic condition, knockdown of MTHFD2 in CRC cells and serine hydroxy methyltransferase in Myc-dependent neuroblastoma cells showed significant decrease in NADPH/NADP+ ratios. This lead to increased cellular ROS and triggered hypoxia-induced cell death [78,79] Moreover, inhibition of MTHFD2 in human xenograft and MLLAF9 mouse leukemia models revealed decreased leukemia burden and prolonged survival [80]. 2.3. Nicotinamide adenine dinucleotide reduced (NADH)/Nicotinamide adenine dinucleotide (NAD) NAD+/NADH, a redox couple, actively participate in glycolysis and mitochondrial oxidative phosphorylation, hence is known as a regulator of energy metabolism. Imbalance of these redox ratio leads to oxidative and reductive stress related disorders [81]. Xie et al. [34] found a significant increase in oxygen consumption in FH/LDH-A deficient cells to maintain NADH/NAD+ ratio which further indicates high oxidative phosphorylation (OXPHOS) activity. They observed a low NADH/ NAD + ratio which could be due to a decrease in LDH-A driven competitive reactions that push more NADH into mitochondria [34] NAD+/NADH ratio was found to be decreased in CI deficient cells which is due to low consumption of NADH in absence of CI [23] Lower consumption of NADH results in NADH accumulation causing allosteric inhibition of α-KG dehydrogenase and accumulation of α-KG. This 4

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selective inhibitor of tumor cell mitochondrial metabolism ultimately causing cancer cell death with high efficiency [120]. A phase I clinical study was conducted with different dose of CPI613, lipoate derivative, in patients with advanced hematological malignancies. 26 human leukemia patients were enrolled and provided CPI-613 as a 2 -h infusion on days 1 and 4 for 3 weeks every 28 days. Out of 21 patients who received at least one cycle of CPI-613, 4 had objective response and 2 achieved prolonged stabilization of disease with no bone marrow suppressed [121]. Pardee et al. conducted another phase I trial of CPI-613 in combination with high dose of cytarabine and mitoxantrone for refractory acute myeloid leukemia (AML). 67 patients were involved in the study. The overall response rate was 50% with median survival of 6.7 months which suggest that the CPI613 sensitized AML cells to chemotherapy [122]. Phase II clinical trial of CPI-613 was performed in relapsed or refractory small cell lung carcinoma. 12 patients were involved and IV infusion of 3000 mg/m2 on days 1 and 4 of week 1–3 of 4week cycle were given. The overall response was very poor, and all 12 patients died with median survival of 4.3 months suggesting that the CPI-613 monotherapy in the dose and schedule tested in the trial was not effective in terms of disease response. The study was closed due to lack of efficacy. Further, they tested CPI-613 in combination with topotecan in 3 patients and found disease response with overall survival of 18.2, 7.4 and 5.1 months. The author suggested to study further to confirm the clinical benefits of combined therapy of CPI-613 with topotecan [123]. Many studies have confirmed the beneficial effects of LA in combination with chemotherapeutic drugs. Recently Nur et al. found synergistic effects of α-LA with cisplatin in MCF-7 breast cancer cells. Apoptosis and oxidant effects of cisplatin has been increased when combined with α-LA by activation of TRPV1 channels [124]. This suggest the possible strategy of combined therapy in the treatment of breast cancer. LA was combined with doxorubicin, a known drug for free radical formation, to observe the effect on experimental murine leukemia L1210. In vitro experiments demonstrated antagonistic effect of LA on doxorubicin in the majority of LA and doxorubicin combination. The synergistic and antiproliferative effect was observed only in relatively high concentrations of both agents. In vivo experiments using both LA and doxorubicin showed increased survival of experimental mice. Further, they observed super-additive effect on survival of leukemic mice with a single combined dose of LA (16 mg/kg) and doxorubicin (5 mg/kg) [125]. Improved long term survival was observed after the patient with adenocarcinoma of the pancreas with metastases to the liver was treated with intravenous LA combined with low-dose naltrexone (ALA-N) protocol. With this result, other patients were put on treatment with ALA-N protocol [126]. Cotreatment of LA with calcitriol significantly reduce the enhancing effect of calcitriol on TNFalpha-induced caspase activation [127]. It was reported that LA changes interleukin-2 (IL-2) concentrations significantly but in the opposite direction in normal and leukemia cells which accounts for LA properties to induce apoptosis in leukemia cells but not in normal cells [113].

2.4. Lipoic acid Alfa-lipoic acid (α-LA) is a naturally occurring cofactor synthesized de novo in mitochondria and present in multi-enzyme complexes: PDC, α-ketoglutarate dehydrogenase complex (KDC), branched chain α-ketoglutarate dehydrogenase, oxoadipate dehydrogenase, and glycine cleavage system [102–104]. LA exists in two forms, lipoic acid (LA, oxidized form) and dihydrolipoic acid (DHLA, reduced form) [103]. PDC activity is regulated by LA through phosphorylation and dephosphorylation of pyruvate dehydrogenase component E1 [104]. Inhibition of pyruvate dehydrogenase kinase by LA results in decreased phosphorylation of E1 leading to increased PDC activity. Moreover, the R-isomer of LA lowers glucose and lactate in diabetic patients via activation and increased oxidation of glucose-derived pyruvate by PDC [104]. Both oxidized and reduced form of LA scavenge various ROS making them useful as an antioxidant in different chronic disorders with high oxidative stress [105]. Previous experiments and clinical studies have found a beneficial effect of LA and its derivatives in many disorders, including cardiovascular disease, diabetes, autoimmune disease, and neurodegenerative disorders [106,107]. The LA/DHLA redox couple has been found as one of the most important and powerful antioxidant systems [106]. The redox potential of LA/DHLA is more effective than other sulfur-containing redox pairs such as GSSG/GSH and cystine/cysteine. DHLA further promotes cellular antioxidant system by reducing cystine levels and indirectly increasing cellular GSH levels. Moreover, they have a high contribution for regeneration of other antioxidant systems including coenzyme Q10 (CoQ10), vitamin C, and vitamin E [108–111]. Many studies have confirmed the cytotoxic and antiproliferative effect of LA in various cancers, such as colon cancer [112], leukemia [113], thyroid cancer [114], and breast cancer [115]. Studies of LA’s effect on fatty acid binding protein 3 (FABP3) overexpressing P19 mouse teratocarcinoma cell line (P19) showed several findings, including elevation of mitochondrial deformation and decreased intracellular ROS production, increased amount of mitochondrial DNA, increased mitochondrial membrane potential, intracellular ATP content and decreased caspase-3 activity [116]. Recently, Yang et al. work demonstrated that α-LA targets epidermal growth factor receptor and growth factor receptor-bound protein 2 (EGFR-Grb2) interaction and induce inhibition of EGFR-MAPK/ERK signaling pathway in NSCLC cell lines. EGFR activation was suppressed and Grb2 level was decreased, limiting cell growth and proliferation. However, the author suggests to explore the precise mechanism of α-LA-mediated disruption of EGFRGrb2 interaction by including a large number and different types of EGFR-mutant cancers cell lines [117]. Choi et al. 2012 investigated the effect of LA in iodine-resistant thyroid cancer (TPC-1) cells and observed the iodine uptake by 1.6-fold via upregulation of sodium iodide symporter (NIS) [118]. Recently, significant anti-cancer effect of alphaLA on thyroid cancer and breast cancer cells was observed. α-LA suppresses thyroid cancer cell proliferation, migration, and invasion through induction of apoptosis and cell cycle arrest by activation of AMPK and subsequent down-regulation of mTOR-S6 signaling pathway [114]. The effect of LA on metastasis of human breast cancer cells was evaluated performing motility, migration, and invasion assay in vitro. Metastasis was significantly inhibited by different doses of α-LA. Authors suggest the mechanism behind this inhibition is likely due to the decreased activity and mRNA expression levels of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) [115]. Recently, a new study observed a similar result and suggest that the inhibition of migration and invasion of breast cancer cells by LA is due to blocking of TGFβ1 signaling pathway. The study further described that non-invasive potential of LA is due to inhibition of extracellular signal-regulated kinase (ERK) and protein kinase B signaling pathway [119]. Moreover, Bingham et al. developed and tested the xenobiotic, non-redox-active analogs of LA, and found to be potent chemotherapeutic agents than the parental LA. The analogs were proven to be

2.5. Coenzyme Q10 CoQ10 is a key coenzyme for ATP generation that primarily transfers electron from CI and complex II (CII) to CIII in mitochondrial ETC (Fig.1). Deficiency of NADH dehydrogenase ubiquinone 1 subunit (Ndufc2), a subunit of CI, has been found in diabetes, cancer, and stroke [128–130]. Recently, CII has attracted a considerable attention as a potential target for cancer. α-tocopheryl succinate (α-TOS) inhibition of succinate binding dicarboxylate site and proximal CoQ10 binding (Qp) site leads to ROS generation from CII and cell death induction in cancer cells in vitro and in vivo [131–133]. Biochemical experiment suggests ubiquinone binding sites in CII as the potential target for α-TOS, rather than FAD sites in its succinate dehydrogenase A subunit. Further, molecular modelling demonstrates the strong interaction of α-TOS with 5

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experiment was performed to observe the combined effect of CoQ10 and glucan in murine experimental autoimmune disease and cancer. CoQ10 showed strong anti-inflammatory effects in all experimental models, both in vivo and in vitro. The effect was more pronounced when CoQ10 was combined with glucan suggesting that this combination could be used in anti-inflammatory and anticancer treatment [161]. Recently. antroquinonol, a derivative of CoQ10 extracted from mushroom, has been found to inhibit cell growth, migration and invasion of human colon cancer [162]. Similar inhibitory effect on migration and invasion has also been observed in breast cancer cells line, MDA-MB231 [163]. Further, the effect of antroquinonol in human lung cancer as well as pancreatic cancer has been investigated. A dose dependent inhibition of cell proliferation has been observed both in human lung adenocarcinoma A549 cells [164] and pancreatic carcinoma cell lines (PANC-1, AsPC-1) [165]. The author stated that the anticancer activity of antroquinonol in pancreatic cancer is due to inhibitory effect on PI3kinase/Akt.mTOR pathway [165]. A phase I multicenter study of antroquinonol on 36 metastatic NSCLC, once-daily dose of 50–600 mg on 4 week cycle (up to 3 cycles), resulted in mild toxicity profile, with no treatment-related mortality suggesting to conduct a phase II study with daily antroquinonol dose of more than 600 mg [166].

both the proximal (QP) and the distal site (QD) of the ubiquinone binding site of CII [131]. CoQ10 function as an intracellular antioxidant preventing mitochondrial membrane proteins and phospholipids from free radical-induced oxidative damage [134,135]. Deficiency of CoQ10 was observed in numerous diseases which could be because of impaired CoQ10 synthesis, a genetic or acquired defects in CoQ10 synthesis, or a utilization of increased CoQ10 consumption [136]. CoQ10 supplementation has found beneficial effects in diabetes [137,138], huntington's disease [139], coronary heart disease [140,141], congestive cardiac failure [142], fibromyalgia [143,144], and cancer [145,146]. Lower levels of CoQ10 were found in plasma as well as tissue of malignant breast cancer patients [147,148]. A previous study conducted on melanoma demonstrated lower levels of CoQ10 in plasma compared to control subjects. These levels were associated with tumor thickness with high CoQ10 concentration in thinner tumors. In addition, they observed that the patients with metastasis had lower CoQ10 levels than those who did not [149]. Many studies have been conducted to observe the effect of CoQ10 in cancer initiation and progression. It has been shown in an in vitro study on C57BL/6 mice that treatment with 100 μM CoQ10 for 72 h. can significantly alleviates pancreatic fibrosis by the ROS-triggered PI3K/ AKT/mTOR signaling pathway [150]. Another in vitro and in vivo study on melanoma cells demonstrated that treatment with CoQ10 inhibit cell growth, induce apoptosis and prevent metastasis through suppression of the Wnt/β-catenin signaling pathway [151]. CoQ10 significantly lowered the growth of prostate cancer cells without affecting noncancer prostate cells [152]. A recent study showed that treatment of human glioblastoma cells with CoQ10 combined with radiation therapy and temozolomide, sensitized cells to radiation-induced DNA damage and potentiates temozolomide cytotoxicity [153]. MMP-2 has a major role in cancer cell division, proliferation, and migration. These enzymes are highly activated in presence of ROS. In vitro study suggests that treatment of breast cancer cell lines with CoQ10 significantly decrease intracellular H2O2 content and inhibit MMP-2 activity leading to lower invasion and metastasis [154]. Doxorubicin is a clinically used adjuvant therapy for breast cancer with high disease-free survival. However, a considerable number of patients develop congestive heart failure which is thought to be due to doxorubicin-induced ROS. To investigate the doxorubicin induced cardiotoxicity, various studies conducted on different cancer cells with different dose of CoQ10 and doxorubicin were summarized in review article [155]. Symptoms like, acute reversible depression of myocardial function and a chronic irreversible cardiomyopathy were prevented by different doses of CoQ10 [155]. Although cardiotoxicity was not accessed, a recent study demonstrated that CoQ10 did not inhibit doxorubicin induced cytotoxicity in breast cancer cell lines [156]. Several clinical studies have investigated the effect of CoQ10 on breast cancer patients. 59patients undergoing chemotherapy were enrolled and provided with CoQ10 (30 mg), branch chain amino acids (2500 mg), and carnitine (50 mg) for 21 days. The efficacy of cancerrelated fatigue was assessed and found to be significantly different between the intervention and control groups [157]. However, in another clinical trial, a group of 236 newly diagnosed breast cancer women were randomized to 3 daily doses of 300 mg CoQ10 or placebo combined with 300 IU vitamin E, added to adjuvant chemotherapy, had no significant improvement on self-reported fatigue or quality of life after 4 weeks of treatment [158]. It has been reported that many chemotherapeutic agents like camptothecin, doxorubicin, etoposide, and methotrexate upregulate COQ4, COQ7, and COQ8 gene expression in non-small-lung cancer cell lines producing high levels of CoQ10. This increase in CoQ10 levels is due to an antioxidant defense system to counteract free radical produced by chemotherapeutic agents [159]. A recent clinical study on hepatocellular carcinoma surgery patients demonstrated that a daily dose of 300 mg CoQ10 supplementation significantly increased antioxidant capacity and reduced the levels of inflammatory markers (hs-CRP and IL-6) [160]. A comprehensive

3. Conclusions In this review, we have explored the biological relevance of some important coenzymes in cancer metabolism. Changed in coenzyme levels have been observed in various cancers. Coenzymes play a key role in regulating enzyme activity to carry out various biochemical reactions. Mutations in metabolic enzymes disrupt normal biochemical reactions and normal organic function leading to several disorders. Thus, role of coenzymes and mutations of metabolic enzymes have gained a considerable attention to investigate the mechanism underlying different disorders. In past years, mutations in CI, FH, SDH, and CIII were identified as common events of cancer cells which are regulated by coenzymes, NADH/NAD+, FADH2/FAD, and Q/QH2 [22–27]. ATP production is downregulated by glycolytic inhibitors such as WZB117 in lung and breast cancer [35] and FX11 in lymphoma and pancreatic cancer xenografts [36]. G6PD overexpression generates high levels of NADPH, that scavenge ROS produced during rapid proliferation of cancer cells. Lower levels of CoQ10 were found in plasma as well as tissue of malignant breast cancer patients [147,148]. The role of coenzymes in cancer treatment has been discussed widely. G6PD inhibition has successfully restored the drug sensitivity on cisplatin resistant cells [75]. Inhibiting 6PGD significantly sensitizes ATC cells’ response to doxorubicin treatment [72]. Many clinical and non-clinical studies have been carried out to inhibit NAMPT expression. Tiazofurin and Selenazofurin incubated with L1210 cells resulted in interference with NAD + synthesis, low cellular NAD+ content, and inhibition of cell growth. GMX1778 and AP0866 are potent small molecules that inhibit NAMPT expression and are already under different phases of clinical trials [90]. Improved long term survival was observed after patients with adenocarcinoma of the pancreas with metastases to the liver was treated with intravenous LA combined with low-dose naltrexone (ALA-N) protocol. CoQ10 significantly lowered the growth of prostate cancer cells without affecting non-cancer prostate cells [152]. As discussed above, there are evidences that showed the associations between coenzymes deficiency and several kinds of cancer. Several coenzymes have already been used in many studies to find the significance of coenzymes in cancer treatment. As a result, most of the studies showed promising and positive outcomes however overall the results are not consistent. In fact, some results are conflicting each other. In addition, beneficial effects from single use of coenzymes or in combination with chemotherapeutic agents have been investigated, combined effects of coenzymes have not been extensively explored. Therefore, considering all the available facts containing majority of 6

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positive preliminary evidences, it seems to put effort on detail investigations on precise molecular roles of these coenzymes in enzyme activity and cancer. Overall, efforts to resolve these coenzyme dependent pathways might provide the new insight to develop a novel therapeutic target for cancer.

[24]

Funding statement [25]

This work was supported by Europeon Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant aggrement No. 722605. Acknowledgments

[26]

We thank all the employees of our company for their helpful discussions. We are grateful to Steven Dearth for his time to do proofreading and Camelia Cauda for guidance with design of the pathway diagram.

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