(568g) Combination Treatments and Mitochondria Damaging Agents: Finding New Uses for Old Drugs

Prostate cancer is the most commonly diagnosed cancer in men and results in the second largest number of fatalities. Poor survival in case of androgen-resistant, metastatic disease necessitates the discovery of novel chemotherapeutics and treatment strategies. Screening of FDA-approved cancer drugs was carried out in order to facilitate the discovery of lead candidates that induced apoptosis in prostate cancer via two treatment pathways: (1) sensitization to the tumor-selective cytokine TRAIL (Tumor necrosis factor Related Apoptosis Inducing Ligand) and (2) mitochondrial depolarization / damage. TRAIL has been shown to selectively induce apoptosis in malignant cells while having reduced toxicity in healthy cells. TRAIL selectively induces apoptosis in cancer cells, but its efficacy is limited by various resistance mechanisms in cancer cells. Such resistance, however, can be overcome with chemotherapeutic treatments that sensitize cancer cells to the TRAIL-induced apoptosis. In this work, FDA-approved anti-neoplastic drugs were screened in order to identify effective lead candidates that sensitized cancer cells to TRAIL. Lead drug candidates identified in the screen were further employed for lead optimization in traditional well plates and also in novel microfluidic cancer cell arrays. Lead optimization involved investigation of the combination treatments over an expanded dose range in different cancer cell lines including those of the prostate, pancreas, and breast. Our investigations were able to identify currently known sensitizers in addition to novel leads whose TRAIL sensitization properties were previously unknown. The screening approach was extended to identify drugs that demonstrated mitochondria damaging activity using a cell-based assay. Mitochondria are key regulators of apoptosis and the release of pro-apoptotic proteins by the mitochondria is considered ?the point of no return? of apoptosis. Direct damage to the mitochondria can facilitate the release of these proteins and induce apoptosis while bypassing any upstream resistances. Our investigation identified currently known mitochondria damaging agents and a previously unknown drug. Taken together, we have identified novel activities for FDA-approved drugs which enhance their utility in different treatment regimes against advanced prostate cancer disease.