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Drug Repurposing in Prostate Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/medsci10010015

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 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.

drug repurposing prostate cancer

1. Prostate Cancer

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]. Metastasis occurs most commonly in regional lymph nodes and bone, followed by lung, then liver [5].
Standard PCa screening consists of measuring the serum prostate-specific antigen (PSA) level and performing a digital rectal exam (DRE); recently, multiparametric magnetic resonance imaging (MRI) has emerged as an additional screening tool [6]. Combining these data with background information, such as family history and race/ethnicity, a shared-decision is usually made between the patient and the urologist on whether or not to pursue prostate biopsy. Prostate biopsy is conducted transperineally or, more commonly, transrectally under ultrasound guidance (TRUS), and it typically consists of 12-core tissue samples that target medial- and lateral- base, mid, and apex regions on both the left and right lobes [7][8].
Clinical staging of PCa combines data from a DRE and needle biopsy results. Though clinical stage correlates closely with pathological stage, pathological stage is the most definitive predictor of biochemical recurrence [9]. Treatment primarily consists of active surveillance (AS), surgery, or radiation, with androgen deprivation therapy (ADT) and chemotherapy used as adjuvants in high-risk disease. AS is a conservative approach considered for patients with Grade group 1 (3 + 3) or 2 (3 + 4) with PSA < 10 ng/mL and involves close monitoring through quarterly PSA tests and an annual prostate biopsy [10]. Patients with Grade group 3 or higher are indicated for definitive therapies: surgery or radiation. High-risk patients, PSA > 20 ng/mL or Grade groups 4 or 5, who choose radiation should receive adjuvant ADT with GnRH agonists or antagonists [11]. High-risk patients with metastasis are managed with ADT and antiandrogens or ADT and docetaxel [12].
Following definitive treatment, 20 to 30% of patients develop biochemical recurrence (BCR) [13][14]. The latter marks the relapse of disease, defined as PSA > 0.2 ng/mL following RP or nadir PSA + 2.0 ng/mL after radiation [12]. Although tumor regression and remission follow ADT, resistance frequently occurs, and in many patients, it is inevitable [15][16]. Resistance to ADT is referred to as castration resistant prostate cancer (CRPC) or hormone-refractory PCa (HRPC). Clinically, patients can progress from non-metastatic CRPC to metastatic CRPC (mCRPC). The role of androgen signaling, as well as other signaling pathways, is important in understanding the mechanisms for CRPC, and using this knowledge facilitates the opportunity for drug targets (Figure 1).
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Figure 1. Clinical diagnosis, patient stratification, and treatment options for prostate cancer. Schematic of the clinical diagnosis and patient stratification for appropriate PCa treatment. Abbreviations: ADT: androgen deprivation therapy; Bx: biopsy; DRE: digital rectal examination; PSA: prostate specific antigen; RP: radical prostatectomy; RT: radiation therapy.

2. Therapy Resistance in Prostate Cancer

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-to-mesenchymal transition, which is believed to be a contributor to therapy resistance in PCa [20][21].
There are various methods for PCa cells to achieve resistance, and some are specific to the modality of androgen deprivation. For example, leuprolide, a GnRH agonist that has been a first line treatment for the last 20 years in ADT, inhibits synthesis of androgens by removing the pituitary’s signal to make testosterone. The tumor cells escape by making their own testosterone in an autocrine fashion. By mutations that drive AR gene amplifications or in certain predisposing polymorphisms (such as short CAG sequences found more often in AA men), the AR becomes more sensitive and can respond to minimal intratumoral levels of testosterone [22]. Abiraterone, a relatively novel agent, can block intratumoral testosterone production, but PCa cells have various routes of resistance. For example, gain-in-function mutations in the AR allow it to use other molecules as ligands, such as those downstream of glucocorticoid or IL-6 transmembrane signaling, in order to translocate into the nucleus and cause gene expression [23]. Enzalutamide, one of the strongest anti-androgen agents, can block AR’s promiscuity with other molecules; however, PCa cells are resilient and eventually continue proliferating, even in the absence of AR activity.

3. Drug Repurposing in Prostate Cancer

3.1. Clinical Challenges in Prostate Cancer

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 [24][25]. 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) [26][27]. Furthermore, as compared to observation or ADT alone, numerous randomized studies have indicated that active treatment improves survival in individuals with high-risk PCa [28][29].
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 [30].
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 [31]. 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 [32][33][34]. 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 [35].
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 [36][37]. Although blood PSA levels associates with clinical stage and tumor phenotype, they are of little use in predicting stage for patients [30][36]. 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) [38][39]. 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 [30][38][40].
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 [41].
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 [35]. 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 [42]. 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 [43][44][45].
Also, false-positive and false-negative biopsies reduce the diagnostic accuracy of PCa [46]. Because of the inherent heterogeneity of PCa [47], current systematic biopsy methods done with TRUS guidance often result in underdiagnosis of PCa [48]. 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 [30][49].

3.2. Drugs Repurposed in Prostate Cancer: From Benchside to Bedside

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 [50][51]. Here, three main categories of drug repurposing studies based on different discovery and validation methods will be discussed (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 anti-cancer 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 [52]. Naftopidil, a selective adrenoreceptor A1D antagonist, is used for treating lower urinary tract symptoms triggered by benign prostatic hyperplasia [53]. 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 [54] (Figure 2).
Table 1. Summary table of the drugs that have been repurposed to be used in prostate cancer in pre-clinical models.
Table
Ref. Drug Original Indication PCa Cell Lines Targeted In Vivo Studies Mode(s) of Action Effect(s)
[55] Propranolol Anti-hypertensive - -
  • Blockade of beta-2 receptors
  • Inhibition of PAP of lipins
  • Halted PCa proliferation
  • Promoted autophagy vesicles and hence cancer cell death
[56] Digoxin Anti-arrhythmic    
  • Inhibition of Na+/K+ ATPase pump which increases intracellular Ca2+ levels
  
[56][57] Ouabain Anti-arrhythmic PPC-1 Male SCID  
  • Sensitize PPC-1 to anoikis, normal apoptosis via detachment from ECM
[58] Aspirin Anti-inflammatory LNCaP  
  • Inhibition of cyclooxygenase (COX) pathway
  • Decreased PG production
  • Reduction of cyclin D1
  • Promote antitumerogenic effects in combination with statins
[59] Celecoxib Anti-inflammatory LNCaP & androgen-nonresponsive PC-3 LNCaP in bovine brain extracts
  • Selective COX-2 blockade
  • Blockade of Akt pathway
  • Induction of apoptosis
[60] dexamethasone Anti-inflammatory DU145 PCa cells  
  • Decreased production of inflammatory mediators
  • Inhibit ERG, an oncogene
  • Decreased proliferation of PCa in an in silico model via ERG inhibition
[61][62][63] Simvastatin Anti-hyperlipidimic PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells DU145R80, 22Rv1 parental and docetaxel resistant cells in xenografts
  • Inhibition of HMG-CoA reductase
  • Sensitization of PCa cells to docletaxil in combination with valproic acid via YES inhibition
  • Promotion of apoptosis via cholesterol depletion
  • Sensitization of anti-androgen resistant CRPC
[64][65][66] Metformin Anti-diabetic    
  • Increased sensitivity to insulin
  • inhibiting hepatic production of glucose
  • Restriction of hepatic gluconeogenesis
  • Decreased growth, proliferation and differentiation by downregulating PI3K axis
  • Decreased ARs, acting as an adjunct to ADT
[67] Glipizide Anti-diabetic PC-3, 22Rv1 and DU145 PC TRAMP transgenic mouse model
  • Stimulation of β-cell insulin secretion
  • Inhibition of angiogenesis by targeting HMGIY/ANGPT1 pathway
[68] Mebendazole Anti-helminthic LNCaP  
  • Inhibition of microtubule assembly
  • Promoting cell death in synergism with docletaxel
[69] Niclosamide Anti-helminthic LNCaP, VCaP, CWR22Rv1, PC3 and HEK293 CWR22Rv1 cells in SCID mice
  • Unclear; uncoupling of oxidative phosphorylation chain
  • sensitize treatment to enzalutamide by decreasing AR-V7
[70][71] Nelfinavir Anti-retroviral DU145 and PC3 cell lines  
  • Inhibition of proteases
  • Combatted CRPC by inhibiting Site-2 Protease (S2P) cleavage and Regulated Intramembrane Processing (RIP)
[72] CMT-3 Anti-microbial Many lines xenografts of PC-3 tumors
  • Inhibition of protein synthesis
  • Promoted apoptosis in PCa cell lines via activation of caspase-3 and caspase-9
[73] Zoledronic acid Bisphosphonate LuCaP 23.1, a PSA-producing human CaP xenograft LuCaP 23.1, a PSA-producing human CaP xenograft
  • Inhibition of bone resorption via inhibition of osteoclast activity
  • Decreased metastatic potential in vivo and induced G1 arrest, proliferation decline and apoptosis in vitro
[74] Valproic acid Anti-epileptic AR-positive (LNCaP and C4-2) and AR-negative (DU145 and PC3) LNCaP, C4-2, and DU145
Xenograft models
  • Inhibition class I histone deacetylases (HDAC)
  • Reduced PCa cellular proliferation and upregulated caspase-2 and caspase-3 activity
[75] Mifepristone Anti-progestational steroid    
  • Anti-progesterone with potent progesterone receptor (PR) affinity
  • Promotion of anti-cancer effects in both androgen sensitive and insensitive PCa, via induction of TFG-beta 1, a pro-apoptotic TF
Abbreviations: AR: androgen receptor; COX: cyclooxygenase; CRPC: castration-resistant prostate cancer; ECM: extracellular matrix; PCa: prostate cancer; PR: progesterone receptor; SCID: severe combined immunodeficiency.
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Figure 2. Drug repurposing in advanced prostate cancer. Using computational approaches and pre-clinical analyses, many Food and Drug Administration (FDA)-approved drugs could be identified and repurposed to treat patients with advanced prostate cancer. Abbreviations: FDA: U.S. Food and Drug Administration; NSAIDs: non-steroidal anti-inflammatory drugs.
Nitroxoline, a widely used antibiotic for treating urinary tract infections, inhibits endothelial cell proliferation for different solid cancer types [76][77]. 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 [78]. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor authorized by the FDA, is typically used in therapies for HIV patients [79]. Studies have identified certain nitroxoline-mediated 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 [80]. Interestingly, nelfinavir shows promising therapeutic potential for the treatment of CRPC through blocking site-2 protease cleavage [71].
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 [81][82]. 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 [83]. 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 [84][85]. Triclosan (TSC) is an approved bactericide in personal hygiene products that possesses a good safety profile, oral bioavailability, and stability in plasma [86]. 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 [85]. 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 [87]. 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 [88].
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 [89]. 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 [90].

3.2.1. Anti-Hypertensives and Anti-Arrhythmic Drugs

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 [91]. One such beta blocker is the non-selective propranolol, which has been shown to exhibit anticancer properties, encompassing PCa [55]. Specifically, it has been shown to halt PCa proliferation and induce apoptosis, in synergism with a glucose analog, 2-deoxy-d-glucose (2DG). Propranolol also acts via inhibition of phosphatidic acid phosphatase (PAP), which has been shown to be overexpressed in certain cancers [92]. 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 [57].
Cardiac glycosides, such as digoxin and ouabain, exert their anti-arrhythmic properties via Na+/K+ ATPase pump inhibition, which increases intracellular Ca2+ levels [57]. 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 [56].
Prazosin is a selective inhibitor of the alpha-1 adrenergic receptor and has been authorized for the treatment of hypertension [93]. Additionally, it is used to treat a variety of clinical conditions, including benign prostatic hyperplasia, Raynaud’s illness, and congestive heart failure [93][94][95]. 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 [96]. Interestingly, prazosin has been shown to display antiproliferative activity, superior to that of other α1-blockers, by inducing G2 checkpoint arrest and subsequent apoptosis in PCa cell lines [97].

3.2.2. NSAIDS, Anti-Inflammatory Drugs and Aspirin

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 [98]. 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 [99]. 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 [58]. Celecoxib, a selective COX-2 inhibitor, blocks Akt phosphorylation and activation, which, in turn, leads to apoptosis in PCa cells [59]. Another anti-inflammatory agent, the glucocorticoid dexamethasone, inhibited ERG activity, an oncogenic transcription factor, of prostate tumor cells in an in-silico model [60].
According to clinical studies, patients undergoing long-term NSAID treatment have a decreased chance of acquiring cancer [100][101]. Indomethacin, an NSAID used for rheumatic disease treatment [102][103], is a notable antineoplastic agent. Mechanistically, it inhibits Cox-1/2-dependent angiogenesis [104][105] as well as MAPK pathways [106]. It also inhibits cancer cell growth via impairing PKC-p38-DRP1 axis-dependent mitochondrial dynamics or downregulating Wnt/β-catenin signaling [107]. 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.

3.2.3. Anti-Hyperlipidemic Drugs

Statins act as lipid-lowering agents by inhibiting the HMG-CoA reductase enzyme and thus inhibiting the rate-limiting step cholesterol biosynthesis [108]. However, preclinical and clinical evidence show that statins exhibit anti-neoplastic activity in various cancers [109][110]. 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 [61][62]. 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 [111]. 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 [63].
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 [112]. Other studies have indicated that statins reduce PCa-related mortality and risk [113][114], while others have found no impact [112]. Inconsistent clinical results make a definite link between statin usage and PCa difficult to establish [115].

3.2.4. Anti-Diabetic Drugs

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 [116]. 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 [64]. By decreasing the levels of insulin in circulation, metformin downregulates phosphoinositide-3-kinase (PI3K) axis, a main contributor to cell growth, proliferation, and differentiation [65]. Furthermore, metformin has been shown to decrease androgen receptor expression, which could establish its role as an adjunct to ADT [66]. 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 [67].
Metformin also has significant anti-cancer activity [117][118][119] in breast, prostate, lung, cervix, ovarian, and CNS cancers, and it is being used in phase 1–4 clinical trials for cancer therapy [120]. Metformin reduced the risk of PCa diagnosis in comparison to other oral hypoglycemics [121]. In xenograft models, the combination of metformin and chemotherapy inhibits tumor development and prevents recurrence of PCa cells via inhibiting inflammatory pathways [122]. 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 [123].
Long-term metformin therapy has also been found to significantly reduce the incidence of breast cancer in women with type 2 diabetes [124]. By reducing elevated insulin levels, metformin inhibits the growth of tumors expressing insulin receptors [125][126]. 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 [127].

3.2.5. Anti-Helminthic Drugs

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 [128]. 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 [68]. 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 [69].
Niclosamide, an FDA-approved antihelminthic drug, exerts an anticancer effect in multiple types of cancer [129][130]. For example, niclosamide inhibits colorectal cancer cells’ liver metastases by downregulating S100A4 and blocking the Wnt/β-catenin signaling pathway [131][132]. 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 [133] and epithelial-mesenchymal transition (EMT) [134], respectively. Furthermore, it inhibits the IL6-STAT3-AR signaling pathways in enzalutamide-resistant advanced PCa cells, reversing drug resistance and cellular invasion [135].

3.2.6. Anti-Retroviral Drugs

Nelfinavir, a protease inhibitor used in HIV combination therapy, has shown potential to be repurposed in cancer therapy [70]. 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) [71].

3.2.7. Anti-Microbial Drugs

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 [136]. 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 [72].
Antifungal itraconazole, which has a high safety profile, has been noted for its anti-angiogenesis properties [137][138]. It inhibits mTOR, which reduces angiogenesis through the cholesterol trafficking route [139]. 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 [140]. In addition, it downregulates the PDGF/PI3K/Akt/mTOR pathway in infantile hemangioma [141]. 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 [137].

3.2.8. Anti-Malarial Drugs

Artemisinin (ARS) is a well-known antimalarial medication that is used to treat about 600 million cases of malaria every year [142]. According to recent research, ARS and its derivatives exhibit anticancer activity as they promote non-apoptotic programmed cell death [143][144][145]. For example, artesunate (ART)-based drugs increased ROS production and favored lysosomal over autophagic ferritin degradation in cancer cells [146].
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 [147][148]. CQ or HCQ, the only FDA-approved autophagy flux inhibitors, have been used to treat pancreatic and other cancers [149][150].
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 [151]. 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 [152][153].

3.2.9. Others

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 [154]. 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 [73]. In regard to PCa, ZA inhibits osteoblastic and osteolytic metastasis [73], while it clinically reduces skeletal complications in PCa patients with bone metastases [155]. 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 [156]. In contrast, the combination of ZA and docetaxel enhanced PCa patients’ survival [128]. 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 [157].
Valproic acid (VPA) is used in the treatment of epileptic, bipolar, and schizophrenic disorders by inhibiting class I histone deacetylases (HDAC) [158]. Xia et al. demonstrated that chronic VPA administration results in reduced PCa cellular proliferation and upregulated caspase-2 and caspase-3 activity [74].
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 [75]. 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 [159]. With combined estrogen treatment, anti-progesterone delivery to PCa cells suppressed the development of androgen-insensitive PCa in vivo [160]. The anti-tumor activity of mifepristone was reported against multiple cancer types, including androgen-sensitive and androgen-insensitive PCa [161]. 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 [162].
Disulfiram was first employed in the rubber vulcanization process, but it has been utilized as an alcohol-aversion medication to treat alcoholism [163][164]. 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 [165]. 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 [166][167]. In addition, ALDH maintains the stemness of cancer cells, which explains disulfiram’s anticancer action in PCSCs [168][169]. 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 [170]. 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) [171]. Additionally, enhanced reduction in tumor growth was obtained upon the combination of disulfiram with Cu2+ in CRPC xenografts [172]. In addition, diocarb (disulfiram metabolite) and copper complex may potentially target NPL4 protein to regulate protein turnover of tumorigenesis, promoting stress-response pathways [173].
Rapamycin has been repurposed for cancer therapy after being authorized as an immunosuppressant for kidney transplantation [174] and an anti-restenosis drug [175][176]. Rapamycin inhibits mTORC1 by binding to the FRB domain of mTOR and hence its use in cancer treatment [177]. Treatment with rapamycin reduced leukemic progenitor cells in patients with acute myeloid leukemia [178][179]. It also demonstrated efficient antitumor activity in patients with drug-resistant chronic myelogenous leukemia, with very minor adverse effects in the majority of cases [180][181]. A study demonstrated that Rapamycin is effective in the in vitro treatment of glioblastoma and neuroblastoma by targeting their CSC population [182].
Thalidomide, a glutamic acid derivative, was used as a sedative in 1957 and to treat morning sickness in pregnant women [183]. 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 [184].
Interestingly, a study 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. 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 [185].

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