Ayse Batova's Research on therapeutics for cancer and inflammatory diseases
Dr. Batova's research centers on experimental therapeutics for cancer and inflammatory diseases. Dr. Batova is particularly interested in investigating the mechanism of action of natural products with selective cytotoxicity to cancer cells with the intention of discovering novel agents and molecular targets to treat refractory cancers.
Natural products have been a great source of many small molecule drugs for various diseases as more than 70% of the current small molecule therapeutics derive their structures from plants used in traditional medicine. The caged Garcinia xanthones is a family of plant metabolites that possess a unique chemical structure, potent bioactivity, and a promising pharmacology for drug design and development. A member of this family, gambogic acid (GA), has shown significant potential as an anticancer agent with its ability to induce apoptosis in multiple tumor cell lines, including multidrug-resistant cell lines, as well as displaying antitumor activity in animal models. Dr. Batova and her collaborators were the first to demonstrate that the primary target of GA is mitochondria as opposed to the transferrin receptor as originally thought. Their results showed that GA induced mitochondrial damage resulting in fragmentation of the mitochondria within minutes of incubation at low micromolar concentrations (Figure 1). Furthermore, a fluorescent derivative of GA was able to localize specifically to the mitochondria and was displaced from these organelles after competition with unlabeled GA. Further work of Dr. Batova demonstrated that an analog of GA, cluvenone, induced ROS and cell stress resulting in the induction of the intrinsic pathway of apoptosis. With these results, Dr. Batova identified GA and cluvenone as new members of mitocans, anticancer agents that act on mitochondria. Specific mitochondrial targets of cluvenone are currently under investigation as well as targets for another natural product, englerin, with highly selective cytotoxicity for renal cancer cells
GA induces immediate mitochondrial fragmentation which results in apoptosis
Figure: HeLa cells were treated with 2μM GA for 0 min (a), 30 min (b), 1h (c), 2h (d) and 3h (e). A first group of cells was processed for IF to visualize the status of the mitochondria (mitochondria are shown in red; nuclei are shown in blue). (f): A second group of HeLa cells was lysed and the level of apoptosis was measured by the presence of cleaved caspase-3 on WB. (g): Human normal skin fibroblast cells (BJ cells) were treated and processed as in (f) and the level of apoptosis was measured by the presence of cleaved caspase-3 on WB. An apoptotic cell, recognizable by the condensed nucleus, is also visible in (e).