Antitubulin drugs: Mechanisms of action and resistance

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DESCRIPTION (provided by applicant): Our overall research initiative is focused on understanding the molecular mechanism of action and resistance to antitumor drugs that target the microtubule (MT) cytoskeleton. MT- targeting drugs are among the most effective agents introduced in cancer chemotherapy. Taxol is the prototype of MT-stabilizing drugs, and its activity in a broad range of human tumors has ignited intense interest in tubulin as a chemotherapy target. The emergence of drug resistant tumor cells, however, limits Taxol's ability to cure disease. Resistance to Taxol is primarily mediated through overexpression of P-glycoprotein (Pgp) and the presence of beta-tubulin mutations. Thus, while tubulin appears to be a very important chemotherapy target, there is an increasing need for novel MT-targeting agents with activity in resistant cells. One such agent is discodermolide, a marine-sponge natural product, with a similarity to Taxol's mechanism of action but with several unique features. Discodermolide has a nontaxane chemical structure and is active against Taxol-resistance cell lines, both those that overexpress Pgp or harbor beta-tubulin mutations. In addition, discodermolide is the only MT-stabilizing drug reported to date to be synergistic with Taxol in various human cancer cell lines. The molecular mechanism of this synergistic interaction, however, is currently unknown. In an effort to better understand how discodermolide and Taxol interact with their intracellular target, tubulin, we have established human cancer cell lines resistant to discodermolide and to the synergistic combination of discodermolide and Taxol. The specific aims of our proposal are :(a) Elucidate the molecular mechanism of resistance to discodermolide or to the discodermolide/-taxol combinations in the drug selected clones. (b) Perform structure-activity relationship (SAR) studies on discodermolide analogs to determine the structural requirements for biological activity. We will also perform molecular modeling and structural studies of discodermolide-tubulin binding (c) Introduce specific tubulin mutations into human cancer cells to investigate their effect on drug-binding.