QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Gapud, E. J. Articles by Hamel, E. Search for Related Content PubMed PubMed Citation Articles by Gapud, E. J. Articles by Hamel, E.

Laulimalide and Paclitaxel: A Comparison of Their Effects on Tubulin Assembly and Their Synergistic Action When Present Simultaneously

Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick; National Institutes of Health; Frederick, Maryland (E.J.G., R.B., E.H.); and Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois (A.K.G.)

Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0°C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine- or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.

Received November 14, 2003; accepted April 1, 2004.

Address correspondence to: Dr. Ernest Hamel, Building 469, Room 104, National Cancer Institute at Frederick, Frederick, MD 21702. E-mail: hamele{at}mail.nih.gov

This article has been cited by other articles:

				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]

				H. Thai, L. Castellano, E. Juneman, H. Phan, R. Do, M. A. Gaballa, and S. Goldman Pretreatment With Angiotensin Receptor Blockade Prevents Left Ventricular Dysfunction and Blunts Left Ventricular Remodeling Associated With Acute Myocardial Infarction Circulation, October 31, 2006; 114(18): 1933 - 1939. [Abstract] [Full Text] [PDF]

				H. Lu, J. Murtagh, and E. L. Schwartz The Microtubule Binding Drug Laulimalide Inhibits Vascular Endothelial Growth Factor-Induced Human Endothelial Cell Migration and Is Synergistic when Combined with Docetaxel (Taxotere) Mol. Pharmacol., April 1, 2006; 69(4): 1207 - 1215. [Abstract] [Full Text] [PDF]

				G. S. Huang, L. Lopez-Barcons, B. S. Freeze, A. B. Smith III, G. L. Goldberg, S. B. Horwitz, and H. M. McDaid Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice Clin. Cancer Res., January 1, 2006; 12(1): 298 - 304. [Abstract] [Full Text] [PDF]