(216f) Identification of Mitochondria Damaging Agents Using Parallel Screening

Prostate cancer is the most commonly diagnosed cancer in men in the US and results in the second largest number of fatalities.  Similarly, pancreatic cancer ranks as the fourth most fatal malignancy in both, men and women; the five-year survival rate is less than 5%.  Unregulated growth and prevalence of cancer cells can be attributed to the shift in the apoptotic mechanism toward cell survival.  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.  Causing direct damage to the mitochondria can facilitate the release of proapoptotic proteins while overcoming upstream resistance to apoptosis.  A small library of antineoplastic drugs was screened in order to identify leads that induced mitochondrial depolarization.  Chemotherapeutic leads were further characterized for their dose-dependent activity in several pancreatic and prostate cancer cell lines.  In addition, we also performed a detailed mechanistic investigation including the kinetics of mitochondrial depolarization, ability to induce reactive oxygen species (ROS), protein release from the mitochondria, and correlation of depolarization with cancer cell apoptosis. Finally, nanoparticles were investigated for delivery of mitochondria damaging drugs to cells with an eye toward improved delivery and targeting.