Daekyu Sun, PhD, believes that angiogenesis, the formation of new blood vessels, promotes tumor growth by providing oxygen and nutrients to proliferating cancerous cells. The switch to an angiogenic phenotype in cancer cells is often mediated by increased expression of the vascular endothelial growth factor (VEGF), which is a pluripotent cytokinine and angiogenic growth factor and is often transcriptionally activated by the transcription factor HIF-1 under hypoxic condition. Some of Dr. Sun’s early work has shown that the G-rich and C-rich strands could form specific G-quadruplex or i-motif structures, respectively, on the polypurine/polypyrimidine tract in the proximal promoter of these genes. That observation led his lab to explore a new therapeutic strategy to repress the transcriptional activation of the human VEGF and HIF-1ï gene with small molecules capable of binding selectively to non-canonical DNA structures formed within the promoter region of these genes.
Another aspect of his work focuses on understanding the chemical and biological mechanisms of the antineoplastic, DNA-damaging natural product leinamycin, in collaboration with Dr. Kent Gates (University of Missouri). Together, they proposed that the unusual DNA-damaging properties of leinamycin would represent a new biochemical route to potent anticancer activity. Thus, the experiments planned in this research are designed to relate leinamycin’s chemical and biochemical properties to its unique biological activity.
Other aspects of Dr. Sun’s research focus on understanding inducible resistant mechanisms in human cancer cells to DNA-damaging anticancer drugs, because the acquisition of chemoresistance toward chemotherapy in cancer cells remains one of the principal obstacles to the effective treatment of malignancies. Some early work showed that DNA ligase I levels are elevated after exposure to a variety of chemotherapeutic drugs, including cisplatin, ara-C, gemcitabine, and topotecan in various human cancer cells. Here the goal is to elucidate the molecular basis and the biological significance of induction of DNA repair genes in human cancer cells in response to major chemotherapeutics in order to identify potential targets appropriate for new anticancer agents that will enhance the lethal activity of many cancer chemotherapeutics.