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.
|Carbonaro, Marisa; Escuin, Daniel; O'Brate, Aurora et al. (2012) Microtubules regulate hypoxia-inducible factor-1? protein trafficking and activity: implications for taxane therapy. J Biol Chem 287:11859-69|
|Kong, Koon Yin; Marcus, Adam I; Giannakakou, Paraskevi et al. (2012) Integrating image analysis algorithms in a web interface for the quantification of microtubule dynamics. Int J Comput Biol Drug Des 5:298-313|
|Kong, Koon Yin; Marcus, Adam I; Giaanakakou, Paraskevi et al. (2011) A Web Interface for the Quantification of Microtubule Dynamics. IEEE Int Conf Bioinform Biomed Workshops 2011:209-214|
|Carbonaro, Marisa; O'Brate, Aurora; Giannakakou, Paraskevi (2011) Microtubule disruption targets HIF-1alpha mRNA to cytoplasmic P-bodies for translational repression. J Cell Biol 192:83-99|
|Zhou, Jun; Vos, Chantal Chanel; Gjyrezi, Ada et al. (2009) The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. J Biol Chem 284:9648-55|
|Escuin, Daniel; Burke, Patricia A; McMahon-Tobin, Grainne et al. (2009) The hematopoietic-specific beta1-tubulin is naturally resistant to 2-methoxyestradiol and protects patients from drug-induced myelosuppression. Cell Cycle 8:3914-24|
|Mun, Jiyoung; Wang, Yuefang; Voll, Ronald J et al. (2008) Syntheses and biological activities of novel 2-methoxyestradiol analogs, 2-fluoroethoxyestradiol and 2-fluoropropanoxyestradiol, and a radiosynthesis of 2-[(18)F]fluoroethoxyestradiol for positron emission tomography. Nucl Med Biol 35:615-22|
|Thomas, Shala L; Zhong, Diansheng; Zhou, Wei et al. (2008) EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle 7:2409-17|
|Marcus, Adam I; O'Brate, Aurora M; Buey, Ruben M et al. (2006) Farnesyltransferase inhibitors reverse taxane resistance. Cancer Res 66:8838-46|
|Nicolaou, K C; Pratt, Benjamin A; Arseniyadis, Stellios et al. (2006) Molecular design and chemical synthesis of a highly potent epothilone. ChemMedChem 1:41-4|
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