This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Flex-Hets, novel classes of conformationally flexible synthetic retinoid that include heteroatoms (O or S) incorporated within the tetrahydronaphthalene structure show great potential in the prevention and treatment of cancer. Flex-Hets induce apoptosis and demonstrate considerably more activity against cancer cells than normal cells. We have observed rapid effects of Flex-Hets on mitochondrial density, membrane integrity, Cytochrome C release, ROS generation and caspace activation, all indicative of the intrinsic apoptosis pathway, in treated A2780 cancer cells. Mitochondria play critical roles in cellular oxidative metabolism through an electron transport system located in their inner membrane. Known inhibitors of mitochondrial NADH oxidoreductase (Complex I) induce apoptosis and increase ROS in a variety of neoplasm. Flex-Hets may represent a new structural class of compounds that induce apoptosis through inhibition of mitochondrial electron transport. Preliminary results from our lab have demonstrated that the lead Flex-Het, SHetA2, inhibits mitochondrial Complex I activity and mitochondrial respiration in a dose dependent manner. However, the exact mechanism of inhibition is not clearly understood.
Our aim i s to categorize the mechanism of Complex I inhibition by FlexHets in sub mitochondrial particles isolated from both cancerous and normal ovarian cells. We will then carry out stead state enzyme kinetic assays to determine the Vmax, km and IC50 (concentration of inhibitor required to affect a 50% inhibition in complex I) of SHetA2 and several related heteroarotinoids compared to several of the know inhibitors such as piericidan A, rotenone or capsaicin.
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