COMBINATION OF MAOA INHIBITORS AND SURVIVIN SUPPRESSANTS: A NEW APPROACH FOR THE TREATMENT OF PROSTAT CANCER

Prostate cancer (PCa) is one of the most lethal type of cancer in occidental countries. A rapid emergence of resistance to commonly used chemotherapeutics results in cancer recurrence and death of patients. Therefore, alternative therapeutic strategies are necessary to be developed. Survivin, a member of the inhibitor of apoptosis proteins (IAP) family, is involved in the regulation of multiple cellular pathways in cancer emergence and progression, including apoptosis suppression and angiogenesis. Expression of survivin contributes to chemoresistance and cancer progression, thus its inhibition could represent a promising approach for PCa treatment. Previously, we discovered a series of novel quinoxalinhydrazide derivatives with desirable physicochemical and drug-like properties and a broad-spectrum anticancer activity. The lead compound of this class, SC144, showed a potent survivin suppressant through the inhibition of the IL-6/gp130/Stat3 signalling axis. In addition, elevated expression of monoamine oxidase A (MAOA) correlates with high-grade PCa, although the molecular mechanisms by which MAOA contribute to the progression of PCa is not yet fully clarified. Thus, survivin and MAOA levels are both elevated in PCa compared to normal prostate gland even though their relationship in PCa is unclear. Herein, we studied the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells. As a result, the combination of MAOA inhibitors (such as Clorgyline) and the survivin suppressants (SC144 or the previously described YM155) showed significant synergism on the inhibition of cancer cell growth, migration and invasion with a concomitant decrease of survivin levels, suggesting a positive feedback loop between survivin and MAOA expression in PCa. Taking into consideration all these results, the synergistic effects of survivin suppressing agents and MAOA inhibitors could represent a promising alternative for the treatment of PCa. References 1Grande, F.; Yamada, R.; Cao, X.; Aiello, F.; Garofalo, A.; Neamati N.; Expert Opin Investig Drugs, 2009, 18(5), 555–568. 2Xu, S.; Adisetiyo, H.; Tamura, S.; Grande, F.; Garofalo, A.; Roy-Burman, P.; Neamati N.; British Journal of Cancer, 2015, 1–10.