This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tinley, T. L. Articles by Mooberry, S. L. Search for Related Content PubMed PubMed Citation Articles by Tinley, T. L. Articles by Mooberry, S. L.

Taccalonolides E and A

Plant-derived Steroids with Microtubule-stabilizing Activity¹

Departments of Physiology and Medicine [T. L. T., D. A. R-H., R. M. L., E. M. J., J. C. Q., S. L. M.] and Organic Chemistry [J. W. C.], Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, and Department of Chemistry, University of Hawaii, Honolulu, Hawaii 96822 [T. K. H.]

During the course of a mechanism-based screening program designed to identify new microtubule-disrupting agents from natural products, we identified a crude extract from Tacca chantrieri that initiated Taxol-like microtubule bundling. Bioassay-directed purification of the extract yielded the highly oxygenated steroids taccalonolides E and A. The taccalonolides caused an increased density of cellular microtubules in interphase cells and the formation of thick bundles of microtubules similar to the effects of Taxol. Mitotic cells exhibited abnormal mitotic spindles containing three or more spindle poles. The taccalonolides were evaluated for antiproliferative effects in drug-sensitive and multidrug-resistant cell lines. The data indicate that taccalonolide E is slightly more potent than taccalonolide A in drug-sensitive cell lines and that both taccalonolides are effective inhibitors of cell proliferation. Both taccalonolides are poorer substrates for transport by P-glycoprotein than Taxol. The ability of the taccalonolides to circumvent mutations in the Taxol-binding region of ß-tubulin was examined using the PTX 10, PTX 22, and 1A9/A8 cell lines. The data suggest little cross-resistance of taccalonolide A as compared with Taxol, however, the data from the PTX 22 cell line indicate a 12-fold resistance to taccalonolide E, suggesting a potential overlap of binding sites. Characteristic of agents that disrupt microtubules, the taccalonolides caused G₂-M accumulation, Bcl-2 phosphorylation, and initiation of apoptosis. The taccalonolides represent a novel class of plant-derived microtubule-stabilizers that differ structurally and biologically from other classes of microtubule-stabilizers.

This article has been cited by other articles:

				A. L. Risinger, E. M. Jackson, L. A. Polin, G. L. Helms, D. A. LeBoeuf, P. A. Joe, E. Hopper-Borge, R. F. Luduena, G. D. Kruh, and S. L. Mooberry The Taccalonolides: Microtubule Stabilizers That Circumvent Clinically Relevant Taxane Resistance Mechanisms Cancer Res., November 1, 2008; 68(21): 8881 - 8888. [Abstract] [Full Text] [PDF]

				C. F. Beyer, N. Zhang, R. Hernandez, D. Vitale, J. Lucas, T. Nguyen, C. Discafani, S. Ayral-Kaloustian, and J. J. Gibbons TTI-237: A Novel Microtubule-Active Compound with In vivo Antitumor Activity Cancer Res., April 1, 2008; 68(7): 2292 - 2300. [Abstract] [Full Text] [PDF]

				S. L. Mooberry, K. N. Weiderhold, S. Dakshanamurthy, E. Hamel, E. J. Banner, A. Kharlamova, J. Hempel, J. T. Gupton, and M. L. Brown Identification and Characterization of a New Tubulin-Binding Tetrasubstituted Brominated Pyrrole Mol. Pharmacol., July 1, 2007; 72(1): 132 - 140. [Abstract] [Full Text] [PDF]

				E. Hamel, B. W. Day, J. H. Miller, M. K. Jung, P. T. Northcote, A. K. Ghosh, D. P. Curran, M. Cushman, K. C. Nicolaou, I. Paterson, et al. Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly Mol. Pharmacol., November 1, 2006; 70(5): 1555 - 1564. [Abstract] [Full Text] [PDF]

				S. L. Mooberry, D. A. Randall-Hlubek, R. M. Leal, S. G. Hegde, R. D. Hubbard, L. Zhang, and P. A. Wender From the Cover: Microtubule-stabilizing agents based on designed laulimalide analogues PNAS, June 8, 2004; 101(23): 8803 - 8808. [Abstract] [Full Text] [PDF]