Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects on cellular microtubules

Ruoli Bai, Susan J. Friedman, George Pettit, Ernest Hamel

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Abstract

Dolastatin 15, a seven-subunit depsipeptide derived from Dolabella auricularia, is a potent antimitotic agent structurally related to the antitubulin agent dolastatin 10, a five-subunit peptide obtained from the same organism. We have compared dolastatin 15 with dolastatin 10 for its effects on cells grown in culture and on biochemical properties of tubulin. the IC50 values for cell growth were obtained for dolastatin 15 with L1210 murine leukemia cells, human Burkitt lymphoma cells, and Chinese hamster ovary (CHO) cells (3,3, and 5 nM with the three cell lines, respectively). For dolastatin 10, IC50 values of 0.4 and 0.5 nM were obtained with the L1210 and CHO cells, respectively. At toxic concentrations dolastatin 15 caused the leukemia and lymphoma cells to arrest in mitosis. In the CHO cells both dolastatin 15 and dolastatin 10 caused moderate loss of microtubules at the IC50 values and complete disappearance of microtubules at concentrations 10-fold higher. Despite its potency and the loss of microtubules in treated cells, the interaction of dolastatin 15 with tubulin in vitro was weak. Its IC50 value for inhibition of glutamate-induced polymerization of tubulin was 23 μM, as compared to values of 1.2 μM for dolastatin 10 and 1.5 μM for vinblastine, Dolastatin 10 noncompetitively inhibits the binding of vincristine to tubulin, inhibits nucleotide exchange, stabilizes the colchicine binding activity of tubulin, and inhibits tubulin-dependent GTP hydrolysis (Bai et al., Biochem Pharmacol 39: 1941-1949, 1990; Bai et al. J Biol Chem 265: 17141-17149, 1990). Only the latter reaction was inhibited by dolastatin 15. Nevertheless, its structural similarity to dolastatin 10 indicates that dolastatin 15 may bind weakiy in the "vinca domain" of tubulin (a region of the protein we postulate to be physically close to but not identical with the specific binding site of vinca alkaloids and maytansinoids), presumably in the same site as dolastatin 10 (the "peptide site").

Original languageEnglish (US)
Pages (from-to)2637-2645
Number of pages9
JournalBiochemical Pharmacology
Volume43
Issue number12
DOIs
StatePublished - Jun 23 1992

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dolastatin 10
Depsipeptides
Antimitotic Agents
Tubulin
Microtubules
Inhibitory Concentration 50
Cricetulus
Cells
Ovary
Vinca
Vinca Alkaloids
Leukemia L1210
Peptides
Burkitt Lymphoma
Vinblastine
dolastatin 15
Poisons
Colchicine
Cell growth
Vincristine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects on cellular microtubules. / Bai, Ruoli; Friedman, Susan J.; Pettit, George; Hamel, Ernest.

In: Biochemical Pharmacology, Vol. 43, No. 12, 23.06.1992, p. 2637-2645.

Research output: Contribution to journalArticle

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