Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy

• Published in: Toxicology and applied pharmacology 2023-11, Vol.478, p.116699-116699, Article 116699
• Main Authors: Khan, Mohammad Afsar, Singh, Deepti, Jameel, Mohd, Maurya, Santosh K., Singh, Swati, Akhtar, Kafil, Siddique, Hifzur R.
• Format: Article
• Language: English
• Subjects: Chemosensitization; Drug resistance; Enzalutamide; Lupeol; Prostate cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2023.116699

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research. [Display omitted] •Lupeol augments Enzalutamide efficacy in chemoresistant CaP cells, both in vitro and in vivo.•Combination therapy inhibits CSCs viability, migration, and oncogene transcriptional activity.•Combination treatment enhance tumor growth inhibition and reduces toxic effects in mice.•Combination treatment modulates Testosterone and methionine metabolite changes.•Lupeol holds potential as an Enzalutamide adjuvant, warranting further investigation.