The <scp>MAO</scp>‐B Inhibitor Selegiline Reduces the Viability of Different Prostate Cancer Cell Lines and Enhances the Effects of Anti‐Androgen and Cytostatic Agents

The current treatments for advanced prostate adenocarcinoma (PAC) include the androgen receptor antagonist enzalutamide and docetaxel-based chemotherapy. Elevated monoamine oxidase-A (MAO-A) mRNA expression and activity in tumorous prostate positively correlate with disease progression and therapy resistance. While MAO-B mRNA expression was also demonstrated in PAC cell lines, its role remained unclear. Therefore, this study evaluates the effects of the irreversible MAO-B inhibitor selegiline and rasagiline and their combinations with conventional therapies on androgen-insensitive (PC-3, DU145) and androgen-sensitive (22Rv1, LNCaP, VCaP) PAC cell lines. MAO activity was determined by the MAO-Glo luminescence assay, viability by the ATP-based chemiluminescence method, proliferation by the Luna-II automated cell counter, and mRNA expressions by RT-qPCR. MAO-B mRNA was stably expressed by all PAC cell lines, with the highest expression in 22Rv1 and LNCaP cells. Selegiline reduced MAO-B activity by 75%-80% and decreased cell counts by 40%-50% at 100 μM in PC-3 and 22Rv1 cells. Selegiline concentration-dependently inhibited cell proliferation (100 μM-10 mM) and reduced viability (1-10 mM) similar to rasagiline in all cell lines. Combination with enzalutamide in 22Rv1, and with docetaxel in PC-3 demonstrated potentiating and additive effects, respectively. Selegiline reduced FOXA1 and GLUT1 mRNA expressions related to cancer progression and metabolism in both cell lines, increased the apoptosis-related BAX in PC-3, and decreased AR, EGFR, and SNAI2 in 22Rv1 linked to proliferation and metastasis. These findings suggest potential for selegiline repurposing in both androgen-sensitive and -insensitive PAC therapy by promoting apoptosis and inhibiting cancer growth and survival signals, respectively.