Drug Repurposing: A New Hope in Drug Discovery for Prostate Cancer

Abstract

Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…On the other hand, it is known that the metabolic pathway of mevalonate is associated with Yes-Associated Protein (YAP) and Tafazzin protein (TAZ), which are related to tumor growth and tumor progression. Thus, statins inhibit HMG-CoA reductase, blocking mevalonate production and inhibiting YAP/TAZ [ 12 ].…”

“…Therefore, statins reduce serum cholesterol levels, and in vitro and in vivo studies indicate that they reduce PC progression and the incidence of lethal PC, improve prognosis and survival rates and decrease the tumor volume and serum levels of the Prostate-Specific Antigen (PSA), and they are also radiosensitizing agents ( Table 1 ). Radiotherapy is one of several standard PC treatments [ 2 , 5 , 10 , 12 ]. In addition to this, statins have demonstrated antiproliferative, anti-inflammatory and antioxidant properties, antitumor effects, an ability to suppress the production of essential metabolites for different cellular functions and for post-translational modification of cell signaling proteins and the capability to inhibit angiogenesis, metastases and tumor proliferation [ 12 ].…”

“…Radiotherapy is one of several standard PC treatments [ 2 , 5 , 10 , 12 ]. In addition to this, statins have demonstrated antiproliferative, anti-inflammatory and antioxidant properties, antitumor effects, an ability to suppress the production of essential metabolites for different cellular functions and for post-translational modification of cell signaling proteins and the capability to inhibit angiogenesis, metastases and tumor proliferation [ 12 ].…”

“…Some of the most important statins that can be repurposed for PC treatment are atorvastatin, fluvastatin, simvastatin mevastatin, lovastatin and rosuvastatin, which can be administered in monotherapy or in combination with other drugs, although recent studies indicate that the main focus is currently on atorvastatin and simvastatin [ 12 ]. In a clinical trial with men with advanced PC, atorvastatin reduced serum PSA levels when compared to the placebo and after 27 days of administration, it decreased the tumor proliferation.…”

“…Moreover, dipyridamole, an antiplatelet agent, when administered in combination with fluvastatin, reduces the amount of fluvastatin needed to induce the death of PC cells. Concerning simvastatin, it is known that it can resensitize PC cell lines that have developed resistance to enzalutamide (a second-generation non-steroidal antiandrogen that competes with androgens for binding sites in the prostate) and that acts through apoptosis caused by cholesterol depletion and inhibition of the Protein Kinase B (Akt) signaling pathway [ 5 , 10 , 11 , 12 , 13 , 14 ]. On the other hand, it also prevents tumor growth, reduces PSA levels and, when administered in combination with irinotecan, suppression of tumor growth and induction of apoptosis caused by inhibition of the MCL-1 protein occur [ 12 ].…”