Repurposing Piroxicam Enhances the Antineoplastic Effects of Docetaxel and Enzalutamide in Prostate Cancer Cells In Vitro

Abstract

Introduction: Ranked second most diagnosed cancer and the fifth leading cause of cancer-related deaths among men, prostate cancer (PCa) constitutes a major medical health issue. Despite the fact that many therapeutic approaches exist against PCa, most cases often develop into a more advanced and lethal stage known as metastatic castration-resistant prostate cancer (mCRPC). Hence, unfolding new therapeutics to treat and manage PCa is of crucial importance. Drug repurposing is a growing research field based on using previously approved drugs with known pharmacokinetic and pharmacodynamic characteristics, for indications other than their traditional ones, like cancer. Non-steroidal anti- inflammatory drugs (NSAIDs) have been studied as anti-neoplastic agents in several malignancies. Objective: In this study, we are interested in assessing the anti-tumorigenic effects of the NSAID Piroxicam (PXM), alone and in combination with conventional therapies, on two PCa cell lines in vitro. Material and Methods: PXM, alone and in combination with conventional therapies (docetaxel and enzalutamide), will be tested on two cell lines established in our laboratory that have the same defined Pten‑/‑TP53‑/‑ background representing two different stages of PCa disease: PLum-AD (androgen-dependent) and PLum-AI (androgen- independent). MTT assay will be performed to screen the cytotoxic effect of a wide battery of PXM concentrations on those two cell lines. Then, trypan blue exclusion assay will be done to study PXM’s effect on cell viability. Afterwards, wound healing will be used to study the ability of PXM in inhibiting cell migration. Furthermore, 3D-sphere formation assay will be performed to assess the effect of PXM in targeting PCa progenitor/stem cells. Results/anticipated results: MTT preliminary results showed that PXM has a dose-dependent cytotoxic effect and a synergistic effect with both conventional drugs on PCa cells. Similar effects are obtained using trypan blue exclusion method. In addition, PXM inhibits and synergistically increases the effect of docetaxel and enzalutamide on migratory index of PCa cells and the sphere-forming abilities of cells. Conclusion: NSAIDs represent a potential candidate to be repurposed against PCa. We expect PXM, an FDA-approved drug, to show anti-cancer effects against PCa cells including progenitor cells, and to enhance the effect of already existing PCa treatments, overcoming resistance obstacles limiting conventional treatments leading to a more efficient management of the disease.