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Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data
Data generated in the new National Cancer Institute drug evaluation program, which is based on inhibition of cell growth in 60 human tumor cell lines, were used to compare new compounds with agents of known mechanism of action in terms of their differential cytotoxicity. Two marine natural products,...
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Published in: | The Journal of biological chemistry 1991-08, Vol.266 (24), p.15882-15889 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Data generated in the new National Cancer Institute drug evaluation program, which is based on inhibition of cell growth in
60 human tumor cell lines, were used to compare new compounds with agents of known mechanism of action in terms of their differential
cytotoxicity. Two marine natural products, halichondrin B and homohalichondrin B, appeared repeatedly when the data base was
probed with known antimitotic agents. We confirmed that both compounds were highly cytotoxic (IC50 values for L1210 murine
leukemia cells of 0.3 and 1 nM, respectively), with accumulation of cells arrested in mitosis at toxic concentrations, that
both inhibited the polymerization of purified tubulin, and that both inhibited microtubule assembly dependent on microtubule-associated
proteins. Limited amounts of homohalichondrin B, the less active agent, were available, so only halichondrin B was studied
in detail. Halichondrin B did not interfere with colchicine binding to tubulin, but it was a noncompetitive inhibitor of the
binding of vinblastine to tubulin (apparent Ki, 5.0 microM). Halichondrin B was therefore compared with other agents which
interfere with the binding of vinca alkaloids to tubulin (vinblastine, maytansine, dolastatin 10, phomopsin A, rhizoxin) in
terms of its effects on tubulin polymerization, inhibition of GTP hydrolysis, inhibition of nucleotide exchange, and stabilization
of tubulin, as well as the quantitative assessment of its effects on vinca alkaloid binding and inhibition of cell growth.
Since halichondrin B was originally isolated from the same organism as the phosphatase inhibitor okadaic acid, and since it
is about 50-fold more effective than okadaic acid as an inhibitor of L1210 cell growth, perturbations of cellular microtubules
observed following treatment with okadaic acid should be interpreted cautiously. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1016/s0021-9258(18)98491-7 |