McGuire, Karen M., Ph.D., May 2012, Biomedical Sciences
Characterization of Apatone and Tolecine Induced Cell Death Mechanisms in Bladder and Ovarian Cancer.
Directors of Dissertation: Chun-che Tsai, Ph.D and James M. Jamison, Ph.D.
Apatone and Tolecine are two novel anti-cancer drugs that have activity against a wide range of cancer cell types including prostate, bladder and ovarian cancer. To further elucidate their mechanisms of action first the physical chemical characterization of the Tolecine series was conducted to reveal a pKa of 9.2 and a log P of 2.3 respectively. Tolecine is structurally similar to resveratrol but with enhanced potency, half-life and selectivity. Further studies into Apatone and Tolecine induced cell death including changes in the lysosome and mitochondria are described. Apatone has been shown to redox cycle in tumor cells producing significant quantities of reactive oxygen species (ROS). Addition of Apatone has also been shown to cause temporary increase in ATP production followed by a rapid decline in ATP levels. This is explained by redox cycling between ascorbic acid and menadione within the mitochondria. This cycling steals electrons from mitochondrial complex 1 and delivers them further down the electron transport chain at cytochrome c. This creates a bypass of complex two and accelerates ATPsynthase production of ATP along with enhancement of ROS production. A proposed mechanism of action for both Apatone and Tolecine are also described.
Committee Members:
Gail C. Fraizer, Ph.D
Gary Meszaros, Ph.D
Gary Kosky, Ph.D