Taccalonolides: Mechanisms of Action and Cellular Resistance

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DESCRIPTION (provided by applicant): Microtubule stabilizers are valuable drugs used in the treatment of cancer. The focus of this project is a new class of plant-derived microtubule stabilizers, the taccalonolides. The taccalonolides have distinct effects on interphase microtubule bundling, mitotic spindle morphology and mitotic signaling pathways. Potent new taccalonolides have been identified for the first time and they robustly polymerize purified tubuli indicating a direct interaction with tubulin/microtubules. The tubulin polymerization experiments also indicate that the taccalonolides interact with tubulin in a manner different from other microtubule stabilizers. Our preliminary data suggest that the taccalonolides bind within a unique site on tubulin. All of the taccalonolides overcome clinically relevant mechanisms of drug resistance and the taccalonolides A and E have in vivo antitumor activity against a paclitaxel and doxorubicin-resistant murine model of breast cancer. Comprehensive studies are proposed to identify the tubulin binding site of the taccalonolides, the functional significance of this bining and how this interrupts mitotic and interphase signaling downstream. These studies are expected to identify a new tubulin binding site or pharmacophore for stabilizing microtubules. The first aim will identify the binding site of the taccalonolides on tubulin/microtubules utilizin complementary structural biology approaches. The second aim describes the functional significance of the taccalonolide interaction with tubulin/microtubules biochemically and in cells. This aim will identify the effects of the potent taccalonolides on purified tubulin and on cellular microtubule dynamics. We anticipate that interruption of microtubule dynamics leads to mitotic signaling and interphase microtubule trafficking defects and ultimately cell death. The last aim will examine the structure-activity relationships of the taccalonolides to identify the specific chemical moieties necessary for optimal biological activities. Information gained from these studies will elucidate the chemical and biological properties of this new class of microtubule stabilizers. This is expected to lead to the identification of a new microtubule stabilizer binding site on tubulin that will provide new opportunities for rational drug development with the possibility of a unique spectrum of activity.