Microtubule stabilizing agents are important 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 a unique mechanism of action. They are the first microtubule stabilizers identified that have Taxol-like effects in cells but they do not bind to tubulin. Comprehensive studies are presented to identify the cellular mechanisms of action and resistance of the taccalonolides. These studies are expected to identify new targets for stabilizing microtubules that can lead to antitumor effects. Information gained from these studies will also identify the signaling pathways invoked by chemically and biologically diverse microtubule stabilizers to initiate mitotic arrest and subsequent apoptosis. This is expected to lead to the identification of new therapeutic targets for cancer. These targets could provide the anticancer efficacy of the taxanes and the ability to circumvent taxane drug resistance and tubulin-related toxicity. The first goal of this effort is to identify the cellular binding site of the taccalonolides. We will test the hypothesis that the taccalonolides bind and inhibit an intrinsic cellular microtubule destabilizing factor resulting in microtubule stabilization. A second goal is to elucidate the mechanisms by which the taccalonolides interrupt mitotic signaling leading to mitotic arrest and apoptosis. We will test the hypothesis that the taccalonolides inhibit Aurora A expression and activity. Drug resistance is a serious problem in the treatment of cancer. We will identify the nature of cellular resistance to the taccalonolides and test the hypothesis that these compounds can circumvent resistance mechanisms that contribute to taxane resistance in the clinic. The ability of the taccalonolides to bypass resistance due to P-glycoprotein expression, tubulin alterations and PXR-mediated resistance will be tested. Cell lines generated by taccalonolide exposure will be evaluated to identify the mechanisms of acquired taccalonolide resistance.
The final aim will identify the structural basis for the taccalonolides mechanisms of action and resistance. Specific chemical constituents important for optimal cytotoxic efficacy and potency, antimitotic actions and antitumor activities will be determined. ? ? ?
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