(621f) Mechanistic Investigation of the TRAIL-Sensitization Activity of Mitoxantrone

In the United States, prostate cancer is the most commonly diagnosed cancer in men, and results in the second largest number of cancer-related fatalities (in men).  Similarly, breast cancer is the most commonly diagnosed cancer in women, and results in the second largest number of fatalities (in women).  Pancreatic cancer ranks as the fourth most fatal malignancy in both, men and women; the five-year survival rate is less than 5%.  Recent studies from our laboratory resulted in the identification of an FDA-approved drug, mitoxantrone, for sensitizing prostate, pancreatic, and breast cancer cells to Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL)-induced death.  Here we report an investigation into the sub-cellular mechanisms by which mitoxantrone sensitizes resistant cancer cells to TRAIL.  In the investigation, kinetic studies were performed to determine the period of time over which sensitization occurred.  The concentrations of apoptosis specific proteins were also measured to identify changes following mitoxantrone treatments.  Additionally, the kinetics of mitochondrial depolarization, generation of reactive oxygen species (ROS), and apoptosis induction were measured to determine the factors that contribute to the activity of the drug.  Finally, nanoparticles were investigated as effective methods of delivering these potent combination treatments to cancer cells, with an eye toward enhancing efficacy and specificity.