key: cord-0787932-y8vdq236 authors: Bahmad, Hisham F.; Demus, Timothy; Moubarak, Maya M.; Daher, Darine; Alvarez Moreno, Juan Carlos; Polit, Francesca; Lopez, Olga; Merhe, Ali; Abou-Kheir, Wassim; Nieder, Alan M.; Poppiti, Robert; Omarzai, Yumna title: Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing date: 2022-02-18 journal: Med Sci (Basel) DOI: 10.3390/medsci10010015 sha: fb1618aedfc7d73e79e1433add0ffd67e76fce25 doc_id: 787932 cord_uid: y8vdq236 Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical’s mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials. In 2022, the United States will have an estimated 268,490 new cases of prostate cancer (PCa) and 34,500 related deaths [1] . Nearly 95% of PCa cases are adenocarcinomas, and 70 to 85% are located in the periphery of the gland [2] . Such tumors tend to extend beyond the prostatic tissue and invade the local perineural space; this histologic finding by itself, though, does not predict positive surgical margins, extraprostatic extension, seminal vesicle invasion, or positive lymph nodes [3] . Lymphovascular invasion, however, was shown to be associated with positive surgical margins, extracapsular extension, seminal vesicle invasion, positive lymph nodes, biochemical recurrence, and decreased overall survival [4] . Physiologically, testosterone passively diffuses into prostate cells where it either directly binds to the androgen receptor (AR) or is converted to dihydrotestosterone, which binds the AR with higher affinity. Bound AR undergoes a conformational change with a dissociation of heat shock proteins, followed by a nuclear translocation, where it dimerizes and serves as a transcription factor that regulates gene expression. In embryology, the prostate does not mature without androgens and becomes atrophic, as seen in individuals with 5 alpha reductase deficiency [17] . The low levels of exposure to androgens are, in fact, protective against development of PCa. The vital role androgens play in PCa was first described by Huggins who showed that prostate tumors regress by removing the primary source of testosterone through orchiectomy [18] . However, deprivation of serum testosterone initially leads to low DHT levels, which is the primary mediator of AR signaling. Withdrawal of these ligands leads to dramatic apoptosis of androgen-dependent tumor cells, leaving a subset of androgen-independent cells in a dormant state [19] , some of which have cancer stem cell (CSC) properties. Additionally, ADT has been shown to alter the dynamics of the prostate tumor microenvironment, affecting stromal, endothelial, and immune cells, as well as promoting epithelial-tomesenchymal transition, which is believed to be a contributor to therapy resistance in PCa [20, 21] . also facilitate resistance to medications targeted towards PI3K/AKT/mTOR pathway [28] . Therefore, the co-administration of drugs targeting multiple signaling pathways can be beneficial. This was demonstrated in a mouse model, where the co-administration of Rapamycin (an inhibitor of mTOR) and Mirdametinib (an inhibitor of MEK) inhibited hormone-refractory PCa cell growth, demonstrating the interdependence of the Ras and AKT signaling cascades in advanced PCa [29] . Another example of dependent cross communication is seen with the gene fusion TMPRSS2-ERG (present in 40 to 80% of PCa) [30, 31] . As with isolated Ras/Raf/MEK/ERK mutations, ERG oncogene requires signaling aberrations from other pathways-such as FOXO1 deletions from AKT dysregulation-to have significant tumorigenic and invasive features [32] . Cross communication between aberrant cell signaling pathways is also paramount to the emergence and maintenance of PCa stem cells (PCSCs) in an androgen-resistant tumor state [33] . Studies have shown that interactions between hypoxia induced factors (HIFs) and PI3K, MAPK, or WNT maintain PCa cell "stemness" [34] . In fact, ADT directly drives the release of hypoxia inducible factors [35] . The presence of PCa stem cells might explain the heterogeneous cell populations seen in prostate tumors. PCSCs are attractive drug targets, as more evidence points to these cells as being the origin of CRPC [33] . Therefore, studies such as our own are necessary to explore available United States Food and Drug Administration (FDA)-approved drugs that can inhibit or slow the progression of the disease. Drug repurposing has always been an opportunistic and fortuitous procedure [36, 37] . For example, sildenafil citrate, often known as "Viagra", was first discovered as an antihypertensive medication, then repurposed by Pfizer for the treatment of erectile dysfunction, based on retrospective clinical experience [38, 39] . Furthermore, thalidomide, which was formerly used to treat morning sickness in pregnant women, was pulled from the market because of its known association with severe bone birth abnormalities in children [40] . However, serendipity led to the repurposing of thalidomide for the treatment of erythema nodosum leprosum (ENL) [41] and later, in multiple myeloma [42] . Currently, the global SARS-CoV-2 (COVID-19) outbreak has given the medication repositioning strategy a new sense of urgency [43] [44] [45] [46] . Traditional drug research is lengthy, owing to the regulations of creating new medications and treatments. Therefore the quicker repositioning technique has piqued attention to identifying compounds that could counteract the consequences of the viral infection including chloroquine [47] , hydroxychloroquine [48] , enalapril [49] , and remdesivir [47] , in addition to others [45] . Drug repurposing, also known as drug repositioning, reprofiling, or retasking, is a strategy for finding new uses for approved or investigational pharmaceuticals beyond their original medical indication [41] . Compared to de novo drug development, drug repurposing offers various advantages over developing a new drug for a specific application. Usually, speeding up pharmaceutical research and development is frequently linked to an increase in the development risk. Repositioning candidates have typically undergone research in preclinical models and human clinical trials, as well as safety assessment, optimization, and sometimes, formulation development and, hence, have well-known safety and pharmacokinetic properties. As a result, the time frame for drug development can be greatly reduced, along with the rate of failure in later efficacy trials [38, 41] . Relative to the stage of development of the repurposing candidate drug, drug repurposing requires less investment in terms of preclinical and phase I and II expenditures, but the regulatory and phase III costs may be comparable to those for a new drug in the same indication [38, 50] . Together, these advantages add up to lower risk and faster return on investment in the development of repurposed pharmaceuticals, as well as lower average associated costs if failures are included. Computational methods, also known as in silico drug repurposing [51] , are critical in predicting novel indications for current medicines, and they largely rely on data from databases such as DrugBank [52] , ChemBank [53] , Genecards [54] , OMIM [55] , and PubMed [56] . As a result of the collection and systematic analysis of diverse data, including gene expression, chemical structure, genotype or proteomic data, or electronic health records (EHRs), innovative approaches for drug repositioning can be developed by emphasizing possible candidates for drug-disease connections [57] . Here, we will discuss the most prevalent computational techniques as well as some examples of medication repurposing. Following the advancements in genotyping technology, reduced genotyping costs, and the completion of the Human Genome Project, genome-wide association studies (GWAS) have been performed to find genetic variants that affect common diseases [58] . Using GWAS, new targets that might be shared across the medicines and disease phenotypes examined could be identified, leading to therapeutic repurposing [59] [60] [61] . In some instances, the genes identified in a GWAS research are not druggable targets. However, a networkbased method may reveal genes that are upstream or downstream of the GWAS-associated target and might be used for repurposing [38, 62] . The network-based method that integrates information on medicines and their druggable targets constructs drug-disease networks based on various data, or indirectly inferred using computational algorithms, to predict new drug candidates [58, 63] . Network-based clustering algorithms were employed to discover subnetworks that allow for prospective candidate drug-target connections [64] [65] [66] . For instance, vismodegib, a known inhibitor of the Hedgehog signaling pathway, was identified to treat Gorlin syndrome [67] , and iloperidone, an antipsychotic for the treatment of schizophrenia, was identified as a novel drug for hypertension [65] . Similarly, network-based propagation techniques are utilized to discover prospective candidate medicines. A random walk propagation algorithm expands a set of disease-associated genes to genes sharing neighbors in a protein-protein network or gene-gene network. Using this strategy, several medicines were identified for novel indications, such as donepezil for Parkinson's disease, methotrexate for Crohn's disease, gabapentin for anxiety disorder, risperidone for obsessive-compulsive disorder, in addition to cisplatin for breast cancer [68] . Functional genomics is also widely used to map cancer dependencies and identify therapeutic targets in cancer. This includes genetic screens based on CRISPR/Cas9 technology [69] [70] [71] , reverse genetic screens, and chemogenomic screens [72] . In PCa, this technology has proven to be crucial for clinicians in their decision-making regarding patient treatment, especially in the era of precision medicine. For instance, suppression of cyclin-dependent kinase 12 (CDK12)-which is essential for PCa cell survival-by the covalent inhibitor THZ531 had an anti-PCa effect by downregulating androgen receptor signaling [70] . Another study using chemogenomic screening demonstrated that Hsp70 co-chaperone DNAJA1 is a hub for anticancer drug resistance [72] . Profile-based drug repurposing serves for the comparison of a drug with another drug, disease, or clinical phenotypes using different profiles of the drug to be repurposed [38, 73, 74 ]. An example is the expression-based profile, also known as a transcriptome (RNA) signature, which allows for drug-drug similarity and drug-disease similarity [75, 76] . The transcriptome signature of a repurposed medication is established by comparing differential gene expression in a cell or tissue before and after therapy, which is then compared to the disease-associated expression profile. For instance, if the drug can reverse the expression pattern of a given set of genes in a particular disease to be closer to that obtained for the healthy state, then that drug might be able to revert the disease phenotype itself. As a result, this computational technique employs the signature reversion principle (SRP), which allows for the comparison of transcriptomic profiles between drugs and diseases and helps in anticipating whether the repurposed drug may be effective on the disease of interest [38, 77, 78] . Additionally, this concept uncovered novel repurposing prospects in a variety of therapeutic domains [79] [80] [81] [82] in addition to chemo-sensitizers in lymphoid malignancies [83] . Furthermore, the expression-based profile concept requires publicly available gene expression databases. The Broad Institute's Connectivity Map (cMap) is derived from the outcomes of treating numerous cell types with over 1300 compounds [84] . However, to make cMap more effective, this resource may be coupled with other public sources of gene expression data, including Gene Expression Omnibus and Array Express [38] . The second type of profile-based approach is the structure-based computational strategy. Since drugs of similar chemical structures may share common biological activity, this strategy relies on the drug chemical structures to compare between drugs and identify the new drug-target association [85, 86] . Using a similarity ensemble approach (SEA), Keiser and colleagues identified 23 new drug-target associations [73] . Another technique used is molecular docking to identify the ligand-receptor association [87] . Conventional docking, for example, involves evaluating numerous ligands (drugs) against a known receptor in a particular disease. Reverse docking, on the other hand, tests drug libraries against a wide spectrum of receptors to find potential interactions [38, 88] . Using a high-throughput computational docking technique, Dakshanamurthy and colleagues have reported that mebendazole, an antiparasitic drug, has the structural capacity to block vascular endothelial growth factor receptor 2 (VEGFR2) [89] . However, this technique is limited due to the lack of 3D structures for some protein targets, lack of macromolecular target databases, a high rate of false positives, some predictability limitations, as well as the questioned docking algorithms utilized due to variances in software packages [38, 76] . Nonetheless, recently, a new promising tool, "Al-phaFold", was developed, which counters this issue of structure prediction. It is a neural network-based computational model that can predict protein structures with atomic accuracy [90] . AlphaFold can be used for molecular replacement and for interpreting cryogenic electron microscopy maps. Importantly, developing accurate protein structure prediction algorithms will accelerate the advancement of structural bioinformatics to keep pace with the genomics revolution. Furthermore, profiling based on side-effect similarities is another resource for computational drug repurposing. Similar side effects between two different drugs are considered to indicate shared physiology, suggesting that they may have a similar mode of action by affecting the same target or pathway [91] . It is also possible that a drug's impact is comparable to that of a certain illness, indicating common drug-disease physiology [92] . Although this is a good technique for identifying repurposing possibilities, the lack of well-defined adverse effect profiles may restrict its application [76] . On the other hand, artificial intelligence technologies capable of text mining and natural language processing may offer future opportunities to overcome these constraints [93] . Some drug repurposing discoveries were made through simple clinical studies or pharmacological analyses, rather than a systematic review of clinical data. Examples of these discoveries are sildenafil for erectile dysfunction [41] , aspirin for colorectal cancer [94] , raloxifene in breast cancer, and propranolol in osteoporosis [95] . Retrospective clinical data is becoming increasingly popular to discover drug repurposing possibilities [96] . Electronic health records (EHRs) are not only a rich source of laboratory test results and prescription information for patients, but they are also a source of indications for drug repurposing [96, 97] . Furthermore, the massive volume of EHR data provides large statistical power [57] . Paik and colleagues have employed this approach to extract clinical data, including laboratory tests and genetic fingerprints, to find over 17,000 known drug-disease correlations and identified terbutaline sulfate as a potential option for the treatment of amyotrophic lateral sclerosis (ALS) [97] . However, obtaining and using EHR data remains challenging due to ethical and legislative hurdles that may limit data access, as well as the difficulty of extracting the unstructured data included in these databases [96] . Text-mining tools, another form of data-based medication repurposing strategy, allows for prioritizing prospective research areas and expedite the disease-drug repurposing process among the extensively accumulating scientific literature [98] . Thus, to discover possible drug-disease connections in the literature, several text mining approaches have been used. In this regard, Li and colleagues have developed disease-specific drug-protein connectivity maps for Alzheimer's disease through combining gene/protein and drug connection information based on protein interaction networks and literature mining. Their approach revealed diltiazem and quinidine as possible therapeutic candidates for Alzheimer's disease [99] . A method to construct sentence graph networks was achieved using text mining techniques to find new sarcoidosis disease targets [100] . In addition, Kuusisto and colleagues introduced KinderMiner as a text mining approach for identifying possible indications of old medicines [98] , while others published an algorithm to identify potential anti-Alzheimer's disease drugs, target, and prioritize them, via systematic 'omics' mining [101] . Lately, researchers and clinicians are exploring drug repurposing to overcome the shortage of medication for novel cancer treatments [102] [103] [104] . As such, repurposing drugs with tolerable side effects and known pharmacokinetics and pharmacodynamics profiles offers an alternative to standard anti-cancer chemotherapeutics [51] . Excellent prospects for drug repurposing have been offered for medicines that may have the ability to address more than one target, as detailed in the next section, thanks to advancements in genomic and proteomic tools. As a result, drug repurposing using non-oncology medications has been applied with medicines that are effective for cancer hallmarks but were not designed originally for cancer treatment. Drug repurposing has many benefits compared to de novo drug studies. These advantages mainly revolve around time and cost, where a study by Kaitin et al. showed that it takes approximately 8.3 years for an anti-cancer medication to get approved, compared with 3 to 4 years for a repurposed drug [105] . Additionally, among the various advantages of drug repurposing is being cost-effective, where a repurposed drug is estimated to cost USD 300 million to reach market, compared with USD 2-3 billion for studying a new chemical entity [104, 106] . A major issue with low-risk PCa is that it is frequently overtreated, whereas high-risk PCa is frequently undertreated. Many individuals with high-risk illnesses are only offered palliative androgen deprivation therapy (ADT) rather than intense local therapy. According to the CaPSURE database, ADT is given to 41% of high-risk patients, whereas RP and RT are given to 24% and 28% of high-risk patients, respectively [107, 108] . In contrast, local therapy, with either RP or RT, depending on the classification of high-risk illness, results in a 49-80% progression-free probability (PFP) [109, 110] . Furthermore, as compared to observation or ADT alone, numerous randomized studies have indicated that active treatment improves survival in individuals with high-risk PCa [111, 112] . Another challenge is choosing the appropriate treatment along with the proper timing of administration. When androgen blocking is used as first-line therapy, for example, high response rates are attained; nonetheless, most men proceed to CRPC. Furthermore, systemic chemotherapies have been proven to improve clinical outcomes in individuals with hormone-refractory PCa. However, they are not curative [113] . Furthermore, despite early detection and intervention, advanced PCa might metastasize to lymph nodes and bones, lowering the quality of life and decreasing the median survival rate [114] . As a result, detecting bone metastases is crucial in clinical practice, since the beginning of bone metastasis frequently necessitates the start of chemotherapy and/or bone-targeted treatment [115] [116] [117] . Another point of contention in PCa care is the timing of hormonal therapy for patients with increasing PSA who have failed initial treatment, as well as if hormones can give an extra advantage to external beam radiotherapy [118] . On the other hand, some challenges in PCa are owed to the limited screening tools and their diagnostic accuracy. Prostate-specific antigen (PSA) is a widely accepted screening tool for PCa. However, elevated PSA levels may result when the normal architecture of the prostate is disrupted, such as in benign prostatic hyperplasia (BPH) and prostatitis. Therefore, PSA is a prostate-specific marker but not PCa-specific [119, 120] . Although blood PSA levels associates with clinical stage and tumor phenotype, they are of little use in predicting stage for patients [113, 119] . Other tests based on PSA derivatives are required to improve on standard blood PSA, such as PSA density, velocity, and age-specific reference range, and PSA isoforms such as free PSA, pro-PSA, and BPSA (benign PSA) [121, 122] . Furthermore, while widespread PSA screening has resulted in early detection and a considerable reduction in PCa staging at diagnosis, it has also resulted in extra, likely unnecessary biopsies, as well as higher over-detection rates [113, 121, 123] . Moreover, the Gleason score is used to grade biopsies for PCa by histopathological examination of tumor development. Biopsies, on the other hand, may not match the prostatectomy specimen due to sampling issues, as well as the possibility of interobserver variability. In addition, people with morphologically similar PCa may behave differently due to inter-and intra-tumor heterogeneity [124] . Several techniques are available to help determine a patient's life expectancy; however, their estimation accuracy is limited. Actuarial life tables, which are readily available, offer a fair estimate, but they do not take into consideration specific medical comorbidities [118] . Comorbidity indices, such as the Charlson comorbidity index, predict life expectancy depending on medical conditions; however, it may ignore or exaggerate the relevance of certain morbidities [125] . Nomograms, on the other hand, may offer more precise predictions with a prediction accuracy of 69-84% for life expectancy after therapy for localized PCa [126] [127] [128] . Also, false-positive and false-negative biopsies reduce the diagnostic accuracy of PCa [129] . Because of the inherent heterogeneity of PCa [130] , current systematic biopsy methods done with TRUS guidance often result in underdiagnosis of PCa [131] . To address these limitations, more sensitive and selective serum-tissue biomarkers should be developed, in addition to conjugating new imaging technologies with standard TRUS, to increase biopsy sensitivity [113, 132] . Conventional anti-cancer chemotherapeutic agents have well-known side effects that severely impair cancer patients' quality of life. Therefore, drug repurposing is an effective alternative method for identifying new anti-cancer candidates from the existing pharmacological pool [51, 133] . Here, we will discuss three main categories of drug repurposing studies for PCa based on different discovery and validation methods ( Table 1 ). The first category is classified based on the knowledge and ability of medical practitioners or researchers to organize scientific observations of random events. For instance, ormeloxifene, a clinically approved selective estrogen receptor modulator, exhibits anticancer properties in multiple cancers including ovarian, head and neck, and breast cancers. However, Hafeez et al. reported ormeloxifene-mediated inhibition of oncogenic β-catenin signaling and EMT progression in PCa, mainly by repressing N-cadherin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and inducing pGSK3β expression. In addition, treatment with ormeloxifene inhibited tumorigenic, metastatic, and invasive capacity of PCa cells in vitro and reduced prostate tumors in xenograft mouse models [134] . Naftopidil, a selective adrenoreceptor A1D antagonist, is used for treating lower urinary tract symptoms triggered by benign prostatic hyperplasia [135] . It is also shown to improve the efficiency of radiotherapy (RT) treatment in PC-3 xenograft models as compared with monotherapy with naftopidil or RT [136] (Figure 2 ). the coal mine roadway to the greatest extent and improve the point cloud registration effect. 2. Perform average error processing on UWB data to reduce its measurement error, connect it to the IMU pose node as a univariate hyperedge constraint and obtain more accurate positioning results by updating the sliding window. The balance of the article is organized as follows: Section 2 introduces the relevant work, Section 3 expounds the methods, Section 4 sets out the experimental results, and Section 5 summarizes and analyzes the article. Nitroxoline, a widely used antibiotic for treating urinary tract infections, inhibits endothelial cell proliferation for different solid cancer types [158, 159] . It also mediates AMPK-dependent inhibition of the mTOR signaling pathway and cyclin D1-Rb-Cdc25A axis suggesting its potential role for therapeutic development against PCa [160] . Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor authorized by the FDA, is typically used in therapies for HIV patients [161] . Studies have identified certain nitroxolinemediated anti-cancer mechanisms, such as inhibition of (PI3K)/Akt signaling pathway, the proteasome, and HIF-1α which limit angiogenesis, as well as activation of endoplasmic reticulum (ER) stress, autophagy, and apoptosis [162] . Interestingly, nelfinavir shows promising therapeutic potential for the treatment of CRPC through blocking site-2 protease cleavage [153] . Second are the drugs that have been evaluated in assays and categorized according to their activity. Itraconazole, the antifungal drug, which inhibits angiogenesis and the Hedgehog signaling pathway, has been tested in phase II clinical trials and found effective in men with metastatic CRPC. In addition, digoxin was repurposed for PCa treatment as it inhibits HIF-1α synthesis and tumor growth and was clinically trialed in patients with recurrent PCa [163, 164] . Clofoctol, an antibiotic used to treat upper respiratory tract infections, is a promising inhibitor of PCa. Wang and colleagues reported that clofoctol reduced the development of PCa cells at clinically feasible doses. It also induced ER stress and activated all three Unfolded Protein Response (UPR) pathways, resulting in indirect suppression of protein translation and subsequent reduction in the amounts of G1/S cyclins, resulting in G1 cell cycle arrest. Furthermore, clofoctol was found to be effective in a PCa xenograft model in animals, making it a promising anti-PCa medication candidate suitable for human testing [165] . Several fatty acid synthase (FASN) inhibitors, including antifungal agent cerulenin, its synthetic derivative C75, and triclosan have been shown to inhibit cancer cell growth by inducing cell death. However, their evaluation in clinical trials was challenged due to pharmacological limitations [166, 167] . Triclosan (TSC) is an approved bactericide in personal hygiene products that possesses a good safety profile, oral bioavailability, and stability in plasma [168] . Triclosan was found to be a superior alternative to C75 and orlistat in triggering cell death in PCa cells via the inhibition of FASN. In addition, it induced G0/G1 cell cycle arrest and dose-dependent reduction in total lipid content of PCa cells [167] . As a result, TCS-mediated suppression of the metabolic oncogene FASN has the potential to be developed as a treatment for advanced PCa. Other drugs are classified using the in-silico drug repurposing approach. For example, risperidone, an antipsychotic agent, is used for the treatment of central nervous system disorders owing to its binding affinity for dopamine D2 and serotonin 5-HT2 receptors [169] . On the other hand, 17-β-hydroxysteroid dehydrogenase 10 (17HSD10) is responsible for Alzheimer's disease pathogenesis and PCa cell survival upon ADT. Since risperidone targets 17HSD10, it is a possible treatment choice for both Alzheimer's disease and PCa [170] . Furthermore, Zenarestat, an aldose reductase inhibitor, may be an effective cancer chemotherapeutic drug since aldose reductases promote tumor development by activating the transcription of NF-kB and AP-1 [171] . Based on thorough gene expression profiling and disease-gene-drug association data, zenarestat was repurposed to serve as a potential medication for treatment in PCa [172] . Beta-blockers act by blockage of beta-adrenergic receptors in the body and have been traditionally utilized for their anti-hypertensive and anti-arrhythmic properties [173] . One such beta blocker is the non-selective propranolol, which has been shown to exhibit anticancer properties, encompassing PCa [137] . Specifically, it has been shown to halt PCa proliferation and induce apoptosis, in synergism with a glucose analog, 2-deoxy-dglucose (2DG). Propranolol also acts via inhibition of phosphatidic acid phosphatase (PAP), which has been shown to be overexpressed in certain cancers [174] . After induction by 2DG, propranolol's blockade of PAPs leads to accumulation of LC3-II and p62, markers of autophagy, thus promoting cancer cell death [139] . Cardiac glycosides, such as digoxin and ouabain, exert their anti-arrhythmic properties via Na + /K + ATPase pump inhibition, which increases intracellular Ca 2+ levels [139] . Simspon et al. showed that ouabain sensitized resistant prostate adenocarcinoma cells (PPC-1) to aniokis, the process by which normal cells undergo apoptosis by detaching from the extracellular matrix (ECM) via a caspase-dependent mechanism [138] . Prazosin is a selective inhibitor of the alpha-1 adrenergic receptor and has been authorized for the treatment of hypertension [175] . Additionally, it is used to treat a variety of clinical conditions, including benign prostatic hyperplasia, Raynaud's illness, and congestive heart failure [175] [176] [177] . In patient-derived glioblastoma-initiating cells (GICs), prazosin mediated growth inhibition through inhibiting the PKCδ-dependent AKT signaling pathway compared to neural stem cells that lack PKCδ [178] . Interestingly, prazosin has been shown to display antiproliferative activity, superior to that of other α1blockers, by inducing G2 checkpoint arrest and subsequent apoptosis in PCa cell lines [179] . Non-steroidal anti-inflammatory drugs (NSAIDs) act via inhibition of the cyclooxygenase (COX) pathway, thus limiting prostaglandin (PG) synthesis, and are one of the most widely used drugs for their anti-inflammatory, antipyretic, and analgesic effects [180] . NSAIDs have been shown to affect the proliferative, apoptotic, resistance, and metastatic potential of many PCa cell lines via both COX-dependent and independent mechanisms. The aforementioned results highlight its potential for use in therapy-resistant PCa [181] . An example of the COX-independent mechanism is demonstrated in the antitumorigenic effects of statin and aspirin combination on LNCaP cells, which are androgen-sensitive human PCa cells, via reduction in cyclin D1 levels [140] . Celecoxib, a selective COX-2 inhibitor, blocks Akt phosphorylation and activation, which, in turn, leads to apoptosis in PCa cells [141] . Another anti-inflammatory agent, the glucocorticoid dexamethasone, inhibited ERG activity, an oncogenic transcription factor, of prostate tumor cells in an in-silico model [142] . According to clinical studies, patients undergoing long-term NSAID treatment have a decreased chance of acquiring cancer [182, 183] . Indomethacin, an NSAID used for rheumatic disease treatment [184, 185] , is a notable antineoplastic agent. Mechanistically, it inhibits Cox-1/2-dependent angiogenesis [186, 187] as well as MAPK pathways [188] . It also inhibits cancer cell growth via impairing PKC-p38-DRP1 axis-dependent mitochondrial dynamics or downregulating Wnt/β-catenin signaling [189] . A clinical trial is currently ongoing (ClinicalTrials.gov; NCT02935205) to study the combined effect of hormone therapy using enzalutamide and indomethacin on PCa by lowering the amount of androgen the body makes and/or blocking the use of androgen by the tumor cells. Statins act as lipid-lowering agents by inhibiting the HMG-CoA reductase enzyme and thus inhibiting the rate-limiting step cholesterol biosynthesis [190] . However, preclinical and clinical evidence show that statins exhibit anti-neoplastic activity in various cancers [191, 192] . Ianelli et al. demonstrated the synergistic effects of simvastatin and valproic acid in sensitizing PCa to docletaxel and decreasing resistance rates. This combination method targets the CSCs by inhibiting the action of the Yes-associated protein (YAP) oncogene, a transcriptional regulator implicated in many cancers, including PCa [143, 144] . Zhuang et al. demonstrated that simvastatin acts to promote apoptosis via cholesterol depletion. Specifically, simvastatin acts via depletion of cholesterol-containing lipid rafts of PCa cells, which, in turn, inhibits protein kinase B (also known as AKT) signaling pathway [193] . Statins also have a role in sensitizing PCa cells to ADT. Kong et al. have shown that simvastatin treatment helps to re-sensitize PCa cell lines that have developed resistance to enzalutamide, an FDA approved anti-androgenic agent for the treatment of CRPC [145] . In a retrospective cohort study of men who underwent prostate biopsy, statin decreased risk of PCa and resulted in a better prognosis and reduction in PCa volume and PSA levels [194] . Other studies have indicated that statins reduce PCa-related mortality and risk [195, 196] , while others have found no impact [194] . Inconsistent clinical results make a definite link between statin usage and PCa difficult to establish [197] . Metformin, a member of the biguanide family, acts as an anti-diabetic agent by increasing sensitivity to insulin, inhibiting hepatic production of glucose, and restricting hepatic gluconeogenesis [198] . Aside from its anti-diabetic properties, metformin has shown the potential to be used for its anti-cancer properties, particularly in PCa. Metformin inhibits the mitochondrial complex I of the electron transport chain, which leads to an increase in adenosine monophosphate-activated protein kinase (AMPK), in turn leading to the inhibition of the mammalian target of rapamycin (mTOR) and activation of tuberous sclerosis complex-2, a tumor suppressor gene [146] . By decreasing the levels of insulin in circulation, metformin downregulates phosphoinositide-3-kinase (PI3K) axis, a main contributor to cell growth, proliferation, and differentiation [147] . Furthermore, metformin has been shown to decrease androgen receptor expression, which could establish its role as an adjunct to ADT [148] . Glipizide, another antidiabetic drug that stimulates beta-cell insulin secretion, has shown tumor suppressive effects of PCa cells in a TRAMP transgenic mouse model. It does so mainly via inhibition of angiogenesis, particularly by targeting HMGIY/ANGPT1 signaling pathway [149] . Metformin also has significant anti-cancer activity [199] [200] [201] in breast, prostate, lung, cervix, ovarian, and CNS cancers, and it is being used in phase 1-4 clinical trials for cancer therapy [202] . Metformin reduced the risk of PCa diagnosis in comparison to other oral hypoglycemics [203] . In xenograft models, the combination of metformin and chemotherapy inhibits tumor development and prevents recurrence of PCa cells via inhibiting inflammatory pathways [204] . In addition, metformin and valproic acid (VPA) synergistically suppressed proliferation in both LNCaP (androgen dependent) and PC-3 (androgen independent) cell lines and enhanced apoptosis in patient-derived prostate tumor explants [205] . Long-term metformin therapy has also been found to significantly reduce the incidence of breast cancer in women with type 2 diabetes [206] . By reducing elevated insulin levels, metformin inhibits the growth of tumors expressing insulin receptors [207, 208] . Metformin has also been shown to activate AMPK, a critical energy sensor in cellular metabolism, and to limit cancer cell proliferation via the negative regulation of mTOR needed for tumor survival [209] . Mebendazole is a microtubule inhibiting drug that fights parasitic infections. Docetaxel is a treatment option for metastatic PCa; however, it had a modest effect on increasing the median survival time [210] . Rushworth et al. showed that mebendazole and docetaxel act synergistically to inhibit both in vitro and in vivo tumor growth of murine-derived PCC. This synergism is proposed to be through the inhibition of microtubule assembly at distinct areas, increasing the mitotic blockade of G2/M and thus, promoting cell death [150] . Niclosamide, another anthelminthic drug, has been shown to potently decrease expression of the androgen receptor variant AR-V7, which drives castration resistant PCa (CRPC). Consequently, it has potential to sensitize treatment to enzalutamide, an anti-androgen of the second generation, which is approved for use in treatment of patients with CRPC that are no longer responsive to docetaxel [151] . Niclosamide, an FDA-approved antihelminthic drug, exerts an anticancer effect in multiple types of cancer [211, 212] . For example, niclosamide inhibits colorectal cancer cells' liver metastases by downregulating S100A4 and blocking the Wnt/β-catenin signaling pathway [213, 214] . It decreases lung cancer invasion by inhibiting the S100A4/NF-B/MMP9 axis: 350 reduces both the breast cancer cell pulmonary metastases and metastatic potential of lapatinib-resistant breast cancer cells by inhibiting the STAT3-FAK-Src axis [215] and epithelial-mesenchymal transition (EMT) [216] , respectively. Furthermore, it inhibits the IL6-STAT3-AR signaling pathways in enzalutamide-resistant advanced PCa cells, reversing drug resistance and cellular invasion [217] . Nelfinavir, a protease inhibitor used in HIV combination therapy, has shown potential to be repurposed in cancer therapy [152] . Guan et al. demonstrated that nelfinavir and its analogues help combat CRPC by directly inhibiting Site-2 Protease (S2P) cleavage and Regulated Intramembrane Processing (RIP) [153] . Minocycline, a semi-synthetic tetracycline derivative, was initially given FDA-approval for acne and some STDs, but it was later shown to have other non-antibiotic beneficial properties, including usage in inflammatory diseases [218] . Lokeshwar showed that chemically modified tetracyclines, particularly CMT-3, was able to promote apoptosis in PCa cell lines via activation of caspase-3 and caspase-9 [154] . Antifungal itraconazole, which has a high safety profile, has been noted for its antiangiogenesis properties [219, 220] . It inhibits mTOR, which reduces angiogenesis through the cholesterol trafficking route [221] . Itraconazole binds to the sterol-sensing domain of NPC1 and targets the mitochondrial protein VDAC1 to regulate AMPK and MTOR, resulting in the suppression of cell proliferation and angiogenesis [222] . In addition, it downregulates the PDGF/PI3K/Akt/mTOR pathway in infantile hemangioma [223] . A non-comparative, randomized, phase II study was conducted to evaluate the antitumor efficacy of two doses of oral itraconazole in men with metastatic PCa. Results showed that high-dose itraconazole (600 mg/day) has a modest antitumor activity in men with metastatic CRPC [219] . Artemisinin (ARS) is a well-known antimalarial medication that is used to treat about 600 million cases of malaria every year [224] . According to recent research, ARS and its derivatives exhibit anticancer activity as they promote non-apoptotic programmed cell death [225] [226] [227] . For example, artesunate (ART)-based drugs increased ROS production and favored lysosomal over autophagic ferritin degradation in cancer cells [228] . Similarly, chloroquine (CQ) and its derivative, hydroxychloroquine (HCQ), are antimalarial drugs that also treat several diseases, including rheumatoid arthritis, discoid lupus erythematosus, and systemic lupus erythematosus [229, 230] . CQ or HCQ, the only FDA-approved autophagy flux inhibitors, have been used to treat pancreatic and other cancers [231, 232] . Quinacrine, an antimalarial drug discovered in the 1920s, aids in the treatment of a variety of malignancies, owing to its ability to activate the p53 gene [233] . Mainly, quinacrine induces p53 expression by facilitating the chromatin transcription (FACT) protein complex, which is trapped onto the chromatin, thereby inhibiting CK2-mediated phosphorylation of p53 [234, 235] . Zoledronic acid (ZA), a member of the bisphosphonates class of drugs, inhibits bone resorption via inhibition of osteoclast activity, hence its role in treatment of osteoporosis [236] . This repurposed drug has been approved for clinical use in treating PCa. Corey et al. demonstrated the anti-PCa effects of ZA, both in vivo by decreasing metastatic potential and in vitro by inducing G1 arrest, proliferation decline, and apoptosis [155] . In regard to PCa, ZA inhibits osteoblastic and osteolytic metastasis [155] , while it clinically reduces skeletal complications in PCa patients with bone metastases [237] . Although the treatment with celecoxib, a COX-2 inhibitor, in combination with ZA therapy, is considered complementary for the treatment of advanced or metastatic PCa, it did not improve the survival rate [238] . In contrast, the combination of ZA and docetaxel enhanced PCa patients' survival [210] . Based on early clinical trials, ZA is typically given every three weeks; however, current evidence suggests that giving ZA every 12 weeks results in similar outcomes in men with CRPC bone metastases [239] . Valproic acid (VPA) is used in the treatment of epileptic, bipolar, and schizophrenic disorders by inhibiting class I histone deacetylases (HDAC) [240] . Xia et al. demonstrated that chronic VPA administration results in reduced PCa cellular proliferation and upregulated caspase-2 and caspase-3 activity [156] . Mifepristone, an anti-progesterone with potent progesterone receptor affinity, is used for pregnancy termination. Etreby et al. showed mifepristone's anti-cancer effects in both androgen sensitive and insensitive PCa, via induction of TFG-β-1, a pro-apoptotic transcription factor [157] . In fact, mifepristone's anticancer activity is known for its ability to inhibit tumor growth via blocking the overexpressed cell surface receptors, such as progesterone, estrogen, and glucocorticoid receptors, in CRPC cells [241] . With combined estrogen treatment, anti-progesterone delivery to PCa cells suppressed the development of androgeninsensitive PCa in vivo [242] . The anti-tumor activity of mifepristone was reported against multiple cancer types, including androgen-sensitive and androgen-insensitive PCa [243] . In addition, a phase II study, performed by Taplin et al., suggested that the combination therapy of mifepristone with corticosteroids, ketoconazole, or 5-α reductase inhibitors might prevent the compensatory surge in adrenal androgens in patients with CRPC [244] . Disulfiram was first employed in the rubber vulcanization process, but it has been utilized as an alcohol-aversion medication to treat alcoholism [245, 246] . Disulfiram's mechanisms of action are closely linked to the acetaldehyde dehydrogenase (ALDH)-related cellular metabolic processes. For example, disulfiram-mediated acetaldehyde metabolism is a viable therapeutic target for BRCA1/2-deficient cancer cells [247] . ALDH positive atypical teratoid/rhabdoid tumor cells also had their metabolism decreased by disulfiram. Furthermore, because of its ability to block ALDH, disulfiram inhibits formaldehyde oxidation in cancer cells, resulting in cell death [248, 249] . In addition, ALDH maintains the stemness of cancer cells, which explains disulfiram's anticancer action in PCSCs [250, 251] . Disulfiram serves as a DNA methyltransferase (DNMT1) inhibitor that restores tumor suppressor genes and DNA demethylation in PCa cells. Mainly, it reduces 5-methyl cytosine (5meC) content and methylation in APC and RARB gene promoters [252] . Hence, in a pilot trial for recurrent PCa, Schweizer and colleagues tested for disulfiram in epigenetic therapy via evaluating 5meC content in peripheral blood mononuclear cells (PBMC) [253] . Additionally, enhanced reduction in tumor growth was obtained upon the combination of disulfiram with Cu 2+ in CRPC xenografts [254] . In addition, diocarb (disulfiram metabolite) and copper complex may potentially target NPL4 protein to regulate protein turnover of tumorigenesis, promoting stress-response pathways [255] . Rapamycin has been repurposed for cancer therapy after being authorized as an immunosuppressant for kidney transplantation [256] and an anti-restenosis drug [257, 258] . Rapamycin inhibits mTORC1 by binding to the FRB domain of mTOR and hence its use in cancer treatment [259] . Treatment with rapamycin reduced leukemic progenitor cells in patients with acute myeloid leukemia [260, 261] . It also demonstrated efficient antitumor activity in patients with drug-resistant chronic myelogenous leukemia, with very minor adverse effects in the majority of cases [262, 263] . A study by our group demonstrated that Rapamycin is effective in the in vitro treatment of glioblastoma and neuroblastoma by targeting their CSC population [264] . Thalidomide, a glutamic acid derivative, was used as a sedative in 1957 and to treat morning sickness in pregnant women [265] . Nowadays, thalidomide is widely recognized as an antiangiogenic agent that inhibits VEGF, bFGF, tumor necrosis factor-alpha (TNF-α), and various other pro-angiogenic factors [266] . Interestingly, a study by our group assessed the in vitro and in vivo antitumor properties and mechanisms of action of ST1926 synthetic retinoids in targeting the cancer stem-like cells population of human PCa. Our results revealed that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53-independent apoptosis, and early DNA damage. It also significantly reduced prostate spheres' formation ability in vitro, denoting sufficient eradication of the self-renewal ability of the highly androgen-resistant CSCs [267] . Typically used cancer therapies are known to carry severe side effects. Findings of medications that are not typically used for this disease is encouraging for several reasons: they are already discovered, most have been on the market for a long time, proving their safety, they can help with diagnosing or treating, many are cost-effective when compared to chemotherapy or radiation, and they may improve quality of life, with minimal side effects. This applies to PCa. We have shown that many drugs have been tested in preclinical studies to assess their anti-tumor activity in PCa. However, many of those drugs have already made it into clinical trials. Categories of those medications include anti-inflammatory (both steroidal and nonsteroidal), anti-arrhythmic, anti-diabetic, anti-helminthic, anti-fungal, antibiotics, lipidlowering agents, anticoagulants, bisphosphonates, anti-parasitics, immunomodulators, growth factor inhibitors, farnesyltransferase inhibitors, ribonucleotide reductase inhibitors, polysaccharide, retinoid derivatives, hormones, sugars, cyclic peptides, alpha-keto acids, fatty acids, vitamins, and chemical elements ( Table 2 ). Prostate cancer cells exploit various cell signaling channels to become castration resistant. Blockade of these channels can terminate or slow the growth of resistant tumors. A plethora of drugs designed for other diseases target the channels used by CRPC. Thus, repurposing these drugs to treat PCa will increase the treatment repertoire. Repurposing offers the advantage of bypassing Phase I and II clinical trials and, thus, speeds up drug approval. Many clinical trials have been designed that repurpose drugs to treat PCa, and more will follow. As electronic health records become more integrated, and artificial intelligence and precision medicine advance, more drugs will be strategically repurposed to treat PCa. Drugs that target the nuances of patient-specific tumors will be identified and hopefully improve patient life expectancy, cost of treatment, and quality of life. Functional genomics is also widely used to map cancer dependencies and identify therapeutic targets in cancer. This includes genetic screens based on CRISPR/Cas9 technology [69] [70] [71] , reverse genetic screens, and chemogenomic screens [72] . In the era of personalized medicine, drug repurposing presents an opportunity and should be implicated, using computational genomic and proteomic technologies, to guide clinicians in their decision-making regarding patient treatment. Studies should continue reviewing the current trends of repurposing, as this is an efficient and valuable practice for drug discovery. Cancer Statistics, 2022 Histological and clinical findings in 896 consecutive prostates treated only with radical retropubic prostatectomy: Epidemiologic significance of annual changes Significance of prostate adenocarcinoma perineural invasion on biopsy in patients who are otherwise candidates for active surveillance Evaluation of lymphovascular invasion as a prognostic predictor of overall survival after radical prostatectomy Analysis of bone metastasis of prostatic adenocarcinoma in 137 autopsy cases MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen Standards for prostate biopsy Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk Stratification, Shared Decision Making, and Care Options Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I Management of biochemically recurrent prostate cancer following local therapy Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer Characterising the castration-resistant prostate cancer population: A systematic review Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches Molecular genetics of steroid 5 alpha-reductase 2 deficiency Cancer of the bladder and prostate Mechanisms of Therapeutic Resistance in Prostate Cancer Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating SPDEF and activating CCL2 EMT Markers in Locally-Advanced Prostate Cancer: Predicting Recurrence? Front Androgen receptor gene polymorphisms and risk of prostate cancer: A meta-analysis Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced? Cancers Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer TMPRSS2-ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion Prostate cancer stem cells: Deciphering the origins and pathways involved in prostate tumorigenesis and aggression Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer Hypoxia induced cancer stem cell enrichment promotes resistance to androgen deprivation therapy in prostate cancer Phenotypic vs. target-based drug discovery for first-in-class medicines The discovery of first-in-class drugs: Origins and evolution Drug repurposing: Progress, challenges and recommendations Pfizer's Expiring Viagra Patent Adversely Affects Other Drugmakers Too The tragedy of birth defects and the effective treatment of disease Drug repositioning: Identifying and developing new uses for existing drugs Antitumor activity of thalidomide in refractory multiple myeloma Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence Rapid repurposing of drugs for COVID-19 Drug repositioning is an alternative for the treatment of coronavirus COVID-19 Crosstalk between COVID-19 and prostate cancer Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia Overcoming the legal and regulatory barriers to drug repurposing Recent advances in drug repositioning for the discovery of new anticancer drugs ChemBank: A small-molecule screening and cheminformatics resource database The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses Online Mendelian Inheritance in Man (OMIM(R)), an online catalog of human genes and genetic disorders PubChem Substance and Compound databases Computational drug repositioning: From data to therapeutics Use of genome-wide association studies for drug repositioning New human gene tally reignites debate Novel therapeutics for coronary artery disease from genome-wide association study data Rational drug repositioning by medical genetics Pathway and network-based strategies to translate genetic discoveries into effective therapies Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci Detecting overlapping protein complexes by rough-fuzzy clustering in protein-protein interaction networks Inferring drug-disease associations based on known protein complexes Identification of new candidate drugs for lung cancer using chemical-chemical interactions, chemical-protein interactions and a K-means clustering algorithm Unfolding communities in large complex networks: Combining defensive and offensive label propagation for core extraction DrugNet: Network-based drug-disease prioritization by integrating heterogeneous data Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer CRISPR Screen Contributes to Novel Target Discovery in Prostate Cancer Chemogenomic screening identifies the Hsp70 co-chaperone DNAJA1 as a hub for anticancer drug resistance Predicting new molecular targets for known drugs Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators Transcriptional data: A new gateway to drug repositioning? Exploiting drug-disease relationships for computational drug repositioning Discovery and preclinical validation of drug indications using compendia of public gene expression data Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease Identifying new antiepileptic drugs through genomics-based drug repurposing Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease Identification of small molecules enhancing autophagic function from drug network analysis Docking and scoring in virtual screening for drug discovery: Methods and applications Using reverse docking for target identification and its applications for drug discovery Predicting new indications for approved drugs using a proteochemometric method Highly accurate protein structure prediction with AlphaFold Drug target identification using side-effect similarity Systematic drug repositioning based on clinical side-effects PISTON: Predicting drug indications and side effects using topic modeling and natural language processing Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement Retrospective clinical analysis for drug rescue: For new indications or stratified patient groups Mining electronic health records: Towards better research applications and clinical care Repurpose terbutaline sulfate for amyotrophic lateral sclerosis using electronic medical records A Simple Text Mining Approach for Ranking Pairwise Associations in Biomedical Applications Building disease-specific drug-protein connectivity maps from molecular interaction networks and PubMed abstracts Graph theory enables drug repurposing-how a mathematical model can drive the discovery of hidden mechanisms of action Drug Repositioning for Alzheimer's Disease Based on Systematic 'omics' Data Mining Drug Repurposing in Medulloblastoma: Challenges and Recommendations Drug repurposing towards targeting cancer stem cells in pediatric brain tumors Repurposing of Anticancer Stem Cell Drugs in Brain Tumors Pharmaceutical innovation in the 21st century: New drug approvals in the first decade Can you teach old drugs new tricks? Trends in the treatment of localized prostate cancer using supplemented cancer registry data Use of advanced treatment technologies among men at low risk of dying from prostate cancer Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy Radical prostatectomy for clinically localized, high risk prostate cancer: Critical analysis of risk assessment methods Radical prostatectomy versus watchful waiting in early prostate cancer Radical prostatectomy versus observation for localized prostate cancer Prostate Cancer Imaging Working, G. Challenges in clinical prostate cancer: Role of imaging Biology and clinical management of prostate cancer bone metastasis Bone Targeting Agents in Patients with Metastatic Prostate Cancer: State of the Art Bone-targeting agents in prostate cancer Early use of chemotherapy in metastatic prostate cancer Current clinical challenges in prostate cancer Prostate-specific antigen. Current role in diagnostic pathology of prostate cancer Prostatic specific antigen for prostate cancer detection Newer potential biomarkers in prostate cancer PSA markers in prostate cancer detection Active surveillance for early-stage prostate cancer: Review of the current literature Molecular pathology of prostate cancer The Charlson comorbidity score: A superior comorbidity assessment tool for the prostate cancer multidisciplinary meeting Predicting life expectancy in men with clinically localized prostate cancer Long-term survival probability in men with clinically localized prostate cancer: A case-control, propensity modeling study stratified by race, age, treatment and comorbidities A nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer Screening for prostate cancer: An update Does pT2b prostate carcinoma exist? Critical appraisal of the 2002 TNM classification of prostate carcinoma Trends in Gleason score: Concordance between biopsy and prostatectomy over 15 years Advances in transrectal ultrasound imaging of the prostate. Semin. Ultrasound CT MRI Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic beta-catenin Signaling and EMT Progression Naftopidil for the treatment of urinary symptoms in patients with benign prostatic hyperplasia Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells Propranolol Reduces Cancer Risk: A Population-Based Cohort Study Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression Simultaneous treatment with statins and aspirin reduces the risk of prostate cancer detection and tumorigenic properties in prostate cancer cell lines The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2 A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition The Hippo Pathway in Prostate Cancer Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC) Metformin: A Bridge between Diabetes and Prostate Cancer. Front The anticancer potential of metformin on prostate cancer Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer Anti-HIV drugs for cancer therapeutics: Back to the future? Nelfinavir and nelfinavir analogs block site-2 protease cleavage to inhibit castration-resistant prostate cancer Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture Development of new cathepsin B inhibitors: Combining bioisosteric replacements and structure-based design to explore the structure-activity relationships of nitroxoline derivatives Effect of nitroxoline on angiogenesis and growth of human bladder cancer Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: A crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation HIV protease inhibitors: A review of molecular selectivity and toxicity Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer Pharmacological inhibitors of Fatty Acid Synthase (FASN)-catalyzed endogenous fatty acid biogenesis: A new family of anti-cancer agents? The fatty acid synthase inhibitor triclosan: Repurposing an anti-microbial agent for targeting prostate cancer Triclosan: A critical review of the experimental data and development of margins of safety for consumer products The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia Identification of a 17beta-hydroxysteroid dehydrogenase type 10 steroidal inhibitor: A tool to investigate the role of type 10 in Alzheimer's disease and prostate cancer Targeting aldose reductase for the treatment of cancer Transcriptomic-Guided Drug Repositioning Supported by a New Bioinformatics Search Tool: GeneXpharma. OMICS 2017 Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well The role of diacylglyceride generation by phospholipase D and phosphatidic acid phosphatase in the activation of 5-lipoxygenase in polymorphonuclear leukocytes Prazosin and clonidine for moderately severe hypertension Medical therapy for benign prostatic hyperplasia: A review of the literature Prazosin relieves Raynaud's vasospasm The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCdelta-dependent inhibition of the AKT pathway Prazosin displays anticancer activity against human prostate cancers: Targeting DNA and cell cycle Prostate Cancer and Aspirin Use: Synopsis of the Proposed Molecular Mechanisms Phase II trial of interleukin 1 alpha and indomethacin in treatment of metastatic melanoma Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: A multicenter phase II clinical trial Analgesic effect of indomethacin shown using the nociceptive flexion reflex in humans Indomethacin in the Treatment of Rheumatic Diseases COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: Synthesis, biological evaluation, and mechanism investigation Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling Indomethacin impairs mitochondrial dynamics by activating the PKCzeta-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells Targeting Mevalonate Pathway in Cancer Treatment: Repurposing of Statins. Recent Pat. Anti-Cancer Drug Discov The role of statins in cancer therapy The statins as anticancer agents Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts Statin use and risk of prostate cancer in a population of men who underwent biopsy Association of statin and nonsteroidal anti-inflammatory drug use with prostate cancer outcomes: Results from CaPSURE Statin use and fatal prostate cancer: A matched case-control study Clinical Potential of Statins in Prostate Cancer Radiation Therapy The mechanisms of action of metformin Metformin and reduced risk of cancer in diabetic patients Metformin and Prostate Cancer: A New Role for an Old Drug Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells Metformin: Taking away the candy for cancer? Metformin use and prostate cancer risk Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors Overcoming Drug Development Bottlenecks With Repurposing: Repurposing biguanides to target energy metabolism for cancer treatment Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion Beyond an antihelminthic drug Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model Niclosamide inhibits epithelialmesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer Targeting androgen receptor versus targeting androgens to suppress castration resistant prostate cancer Minocycline: Far beyond an antibiotic Repurposing itraconazole as a treatment for advanced prostate cancer: A noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer Hedgehog signalling in prostate regeneration, neoplasia and metastasis The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis Itraconazole Induces Regression of Infantile Hemangioma via Downregulation of the Platelet-Derived Growth Factor-D/PI3K/Akt/mTOR Pathway Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: An open-label randomised trial Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety in pregnancy Steady-state pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus Autophagy as a target for anticancer therapy Targeting autophagy in cancer Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors Curaxins: Anticancer compounds that simultaneously suppress NF-kappaB and activate p53 by targeting FACT Role of Chromatin Damage and Chromatin Trapping of FACT in Mediating the Anticancer Cytotoxicity of DNA-Binding Small-Molecule Drugs Intravenous zoledronic acid for the treatment of osteoporosis: The evidence of its therapeutic effect A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naive Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial Duration of suppression of bone turnover following treatment with zoledronic acid in men with metastatic castration-resistant prostate cancer Valproic acid pathway: Pharmacokinetics and pharmacodynamics Systems pharmacology of mifepristone (RU486) reveals its 47 hub targets and network: Comprehensive analysis and pharmacological focus on FAK-Src-Paxillin complex Suppression of the growth of the androgen-insensitive R3327 HI rat prostatic carcinoma by combined estrogen and antiprogestin treatment Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones The status of disulfiram: A half of a century later A drug sensitizing the organism to ethyl alcohol BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity Human Endogenous Formaldehyde as an Anticancer Metabolite: Its Oxidation Downregulation May Be a Means of Improving Therapy Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer Copper signaling axis as a target for prostate cancer therapeutics Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4 Sirolimus after kidney transplantation Oral everolimus inhibits in-stent neointimal growth Drug-eluting stents in vascular intervention Rapamycin passes the torch: A new generation of mTOR inhibitors Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors 001 (everolimus) prevents mTOR and Akt late re-activation in response to imatinib in chronic myeloid leukemia Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma Thalidomide and dexamethasone: A new standard of care for initial therapy in multiple myeloma Thalidomide in cancer medicine The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem-like cells The authors declare no conflict of interest.