Thu, 2010-12-23 12:00 - 13:00
Seminar Hall, Central Department of Botany, TU
Ottelione A: A Natural Product with Potent Anticancer Activity, Mode of Action and Molecular Basis for Resistance
Ottelione A, a natural product isolated from Ottelia alismoides, exhibits potent antitumor activity (LC50 values 25-60 nM) against a panel of breast tumor cell lines. Its antitumor activity is believed to be due to the inhibition of microtubule assembly during mitosis and thus commit cells to apoptosis. Our studies show that any structural modifications to Ottelione A will result in significant loss of antitumor activity (LC50 values 0.075-30 µM) against the panel of breast tumor cells tested. A human breast adenocarcinoma cell line (MCF 7/OttA) resistant to ottelione A, is also resistant to Ottelione A structural analogues as well as other microtubule assembly inhibitors/destabilizing agents. Molecular analysis of MCF-7/OttA cells suggests the resistance is due to multi-factorial changes in the resistant cells. Over-expression of ABCG2 (a member of multi-drug resistance family protein) and mislocalization of mitotic arrest deficiency proteins, e.g., MAD1 and MAD2, partly account for resistance to Ottelione A. Microarray analysis of parent (MCF-7/0) and Ottelione A resistant MCF-7/OttA cell lines performed using a human cancer and drug metabolism gene array shows significant differences in gene expression patterns. Further studies related to mechanisms of cellular sensitivity to Ottelione A are on-going.