Prostate Cancer: Drug Discovery and Development

Introduction

Drug discovery and development involve a number of stages to develop a novel drug, therefore a reduction in time frame new approach is developed which is repurposing of existing drugs. Till to date, the importance of drug repurposing is significantly increased to identify new use of the pre-existing drug. Repurposed of the drug can be achieved by two methods, one is unintentionally and another by systemically (Parvathaneni, Kulkarni, Muth and Gupta, 2019). Drug repurposing is one type of drug recycling, to treat except the original one. For the new drug approximately 15 years can be taken place to bring it in the market as compared to repurposed drug takes only 3 to 12 years (Dey, 2019). This literature review is about drug repurposing with its development, opportunities and challenges. There are a number of methods are developed to identify and validate target of drug repurposing such as, computational and experimental. Both methods are different in lots of way except proteomics and genomics because these two entities make cells and tissues. These Omics are good biomarkers for the accurate treatment of disease. (Talevi, 2018). There are a number of the opportunities of drug repurposing such as, when economic conditions are not good, unclear pathophysiology of rare disease, repurposing method is quick way to identify genetic variation, responsible factors of the disease and identified protein target (Pushpakom et al., 2018). There is low risk of adverse drug reaction and toxicity. Drug repurposing has high success rate i.e. 1/10 as compared to novel drug discovery i.e.1/10000. In the drawback, impairment in patenting new use of existing medicine, sometimes chances of the rejection because of previous toxic, adverse reaction and safety history. There are some strategies to accelerate drug repurposing such as, in silico models, target docking, artificial intelligence (AI). For the promotion of drug repurposing collaboration for bringing new ideas and approaches, corporate social responsibility, social media is also helpful to promote the awareness of drug repurposing (Dey, 2019). The main aim and objective of this literature review is, to review repurposed drugs with their potential as repurposed use including advances and challenges.

Discussion

This literature review includes discussion about the Statins, Digoxin, Exenatide and Itraconazole with their history of link between traditional use and repurposed use, how they act potentially on target as a repurposed drug with their challenges.

Repurposed drugs:

Statins:

Statins are repurposed as an anti-cancer drug because; there is a common link between cardiovascular disease and cancer such as, aging-related, epidemiology and pathophysiology. Both are overlapping on each other in case of biology. Both have similar risk factors for instance, hypertension, obesity, smoke, and type 2 diabetes mellitus. Tissue inflammation is a common reason for the progression of cancer and CVD. Moreover, clonal hematopoiesis is one of the links between both diseases. Before repurposing statin as an anti-cancer drug, it is approved for the treatment of hypercholesterolemia and atherosclerosis by FDA. Statins reduced the production of farnesyl pyrophosphate and geranyl-geranyl phosphate by inhibiting HMG-CoA reductase in the mevalonate synthesis pathway. These both are important for activation of protein G which regulates proliferation, migration, and death of cell. Higher dose of statins shows apoptosis by decreasing the level of anti-apoptotic proteins such as, Bcl-2 and Bcl-xL and inhibition of cancerous cell growth by blocking G beta and gamma dimer in the plasma membrane. Statins shows major benefit in breast and liver cancer. Few investigations done in the use of Statins with combination therapy such as, simvastins combined with irinotecan, 5-flurouracil and leucovorin showed good anticancer activity during phase 2 studies (Gelosa, Castiglioni, Camera and Sironi, 2020). Particularly simvastatins gives adorable result in the case of solid tumor, shown during clinical trial. In the case study of simvastatin shows that , ≥40 mg/day for 2-5 years reduced colorectal cancer. These studies show the potential of Statins as an anti-cancer drug (Kale et al., 2020). Statins shows anti-cancer activity in glioma proven by pre-clinical studies. The activation of ERK and AKT in rat C6 glioma cells is block by mevastatins and simvastatins. In mice, simvastatines caused autophagy and inhibit TGF-β signaling and give relief in glioma, however during a control case study at two centre, Columbia University Medical Center and the University of California San Francisco showed inverse effect with simvastatins with long duration use but there were no risk with rosuvasttin and atorvastatin. More lipophilic statins show best risk reduction. Therefore, it is major challenge in glioma only risk reduction achieved by use of only lipophilic statins (Siegelin et al., 2019).

Digoxin:

Digoxin has the property of cardiac glycoside obtained from foxglove. It is mainly used in the treatment of heart failure and arrhythmia by act as inhibitor of Na+/K+-ATPase pump in cell membrane, thereby increase concentration of ca+2 in Myocardiocytes and pacemaker cells to longer action potential. During the statistic group studies, digoxin shows decreased in the recurrence and aggressiveness of the breast cancer in early 1980s. It act by interfering with signaling of estrogen receptor in cancer cells and suppress the growth of breast cancer. However, after two decades it shows inverse result, the population who were taken a digitoxin had more risk of breast cancer as compared to control group showed by Haux et al. it increases the incident of ER-positive breast cancer rather than ER-negative. In the recent advances, digoxin identified as most potent drug in prostate cancer. It reduces approximately 25% incidence of prostate cancer. It shows 46% reduction in the incidence of prostate cancer after used it for more than 10 year. It acts by inhibiting the secretion of prostate specific antigen in androgen receptor. Most challenging is narrow therapeutic index of digoxin, therefore therapeutic serum level of digoxin is unclear for inhibiting prostate cancer. Recently there are number of the trails ongoing for treatment of the cancer as monotherapy or combination therapy of digoxin (Shim and Liu, 2014).

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Digoxin also inhibit the factor-kappaB and DNA topoisimerase 2, thereby induced apoptosis and act as anti-tumor agent. Another mechanism of digoxin is inhibition of protein suppression, altering signaling pathway of interferon, disruption of mitochondrial activity and calcium based signals. Digitalis is fully evaluated as therapeutic agent and recently, 8 trail are completed, 2 active and 4 are recruiting trails are registered (Kirtonia et al., 2020). Though digoxin reported for an inhibitor of heavily implicated factor in promoting tumor growth- HIF-1 such as, VEGF, GLUT1, HK1 and HK2 for prostate cancer, it shows inversely effect on HIF-1 at therapeutic level in mice as relevant in humans. It shows significant inhibiting effect on prostate cancer (Turanli et al., 2018).

Exenatide:

Exenatide is an agonist of GLP-1(Glucagon-like peptide 1 receptor) approved by FDA for the treatment of the diabetes mellitus.GLP-1 is secreted in the response of the food intake by small intestine and readily metabolized so it is not feasible for outside treatment. Exenatide is long acting analogue of GLP-1. Main expression of glp-1 is in the pancreases, however it also present in brain and its analogues are demonstrated for neuroprotective effect such as, decreases in neuroinflammation as well as increases neurotrophic and neurogenicity. It shows decrease in the loss of SN cell and activity, in addition it also store the striatal dopamine in mice treated with MPTP. Exenatide inhibit neuronal toxicity and prevent the formation of p-tau. According to preclinical study, clinical study is conducted with single blind, in which 45PD patient randomly assigned with exenatide treatment and no exenatide for 12 months. Result comes in the favor of exenatide. Successful single blind study lead to double blind study which shows improvement in motor activity with the group of exenatide. In the challenge of exenatide, it provide only symptomatic relief not disease modifying treatment. Moreover, there is no major outcome in daily routine activity and mood of patient. However, new generation of GLP-1 shows neuroprotective effect in mice. Recently, exenatide effect is assessed in biomarker of progression PD (Guttuso, Andrzejewski, Lichter and Andersen, 2019). Exenatide can cross blood brain barrier and affect pathway of central nervous system such as, neuroinflamation, oxidativestress, neuronal growth and proliferation. Exenatide activate GLP-1 receptor and GLP-1 lead to activation of cyclic adenosine monophosphate thereby it activate protein kinase A and phosphoinoside-3 kinase these all stabilized dendritic spines and promote neuronal survival. (Kakkar, Singh and Medhi, 2018). Exenatide increases anti-inflammatory effect as well as decreses in pro-inflammatory mediators. PT302 is modified formulation of exetanide created by peptron the south corean company. It is slow release formulation by use of the D, L-Lactideco-glycolide. Exenatide micropaticles coated with L-lysine for suppression of burst in injection. In addition, PT302 explore disease modifying effect on Parkinson’s disease. (Foltynie and Athauda, 2020).

Itraconazole:

Itraconazole was anti-fungal agent belongs to the triazole family. It act on cytochrome p450-dependent lanosterol 14-α demethylase, which is paramount in the ergosterol synthesis. Itraconazole act by destructing fungal cell membrane and truncated synthesis of ergosterol. Albeit itraconazole is not more efficacious as anti- fungal, it has potential anti-cancer activity by inverting the p-glycoprotein chemoresistance and adjusting hedgehog and b-catenin pathway of signal transduction. In additament it withal inhibit angiogenesis. Itraconazole shows better result when it coalesces with other chemotherapy for the utilization in pancreatic, ovarian, and breast cancer by truncating endothelial cell proliferation and migration. (Tsubamoto et al., 2017). In the case of itraconazole, it is expeditious for clinical tribulation implementation in sarcomas such as, in osteosarcome by act on hedgehog pathway. Itraconazole damage cholesterol trafficking and inhibits the mTOR and VEGFR2 signaling pathways in endothelial cells suggested by Xu et al. (2010) (Xu et al., 2010). After that, oral itraconazole is evaluated for anti-tumor efficacy for treatment of metastatics CRPC during phase 2 tribulation and suggested that high dose(600 mg/day) has highest anti-cancer activity by suppressed Hedgehog pathway (Antonarakis et al., 2013).

Nilotinib:

Nilotinib used in chronic myeloid leukemia by inhibiting Bcr-Abl tyrosine-kinase fusion. It is 30 times more potent than imatinib. Recently, approved for Philadelphia chromosome CML patient because of the intolerance of the imatinib. In the neurodegenerative disease Abelson non-receptor tyrosine kinase play important role and it can be activated by oxidative process. After the activation of c-Abl it caused accumulation of parkin interacting substrate, thereby produced downregulation of peroxisome proliferator receptor, mitochondrial dysfunction and loss of dopaminergic neurons. Activate c-Abl converte α-synuclein in to the lewy bodies by the phosphorylation (Lindholm et al., 2016). Nilotinib is tested for the treatment on the α-synuclein in rodent and it shown reduction in Abl activity with autophagic α-synuclein clearance. It also improved in dopamine level and motor function (Hebron et al., 2013). Currently nilotibin tested for phase-1 study with PD patient with different doses and it proven safe. Though there are benefit of Nilotinib as repurposed drug, it also has risk of adverse drug reaction and issue of tolerability as challenge. Recently, nilotinib is tested for phase-2 study for further investigation of its treatment in PD. Nilotinib proven as safe in randomized, double blind and placebo control study in the aspect of pharmacokinetics. Therefore, it is an alluring opening to developed repurposed drug for the PD treatment. (Kakkar, Singh and Medhi, 2018)

Conclusion

Drug repositioning is advantageous process as compared to discovery of novel drug. Pharmaceutical and biotech companies indentified knowledge of drug repurposing and there are so many drugs are approved by FDA as repurposing use. Drug repurposing is cost effective, less time consuming, successful method as compared to novel drug discovery process. High success rate as compared to De novo drug. According to discussion of this review it is concluded that, there are significant achievement of the repurposed drug in the anti-cancer therapy such as, Statins which shows good potential as monotherapy as well as combination therapy, Digoxin shows significant result specially in prostate cancer as compared to breast cancer and still trails are ongoing for its combination therapy studies, Itraconazole proven potential in sarcomas. Repurposed drug in Parkinson’s disease such as, Exenatide passes single and double blind trial. Moreover its modified formulation PT302 proven for disease modifying effect, Nilotinib successfully passes phase-1 and phase-2 trail and attributing new opportunity for the treatment of the Parkinson’s disease.

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