LU103793 (NSC D-669356): a synthetic peptide that interacts with microtubules and inhibits mitosis.
LU103793 (NSC D-669356) is a new synthetic derivative of Dolastatin 15, an antiproliferative compound which was isolated from the mollusk Dolabella auricularia. Like Dolastatin 15, LU103793 is highly cytotoxic in vitro (IC50 = 0.1 nM). To investigate the mechanism of action of LU103793, we used a combination of biochemical and cellular methods. Turbidity assays with bovine brain microtubules demonstrated that LU103793 inhibits microtubule polymerization in a concentration-dependent manner (IC50 = 7 microM). Treatment with this compound also induced depolymerization of preassembled microtubules. Cell cycle analysis of tumor cell lines treated with LU103793 indicated a block in the G2-M phase. At the cellular level, it induced depolymerization of microtubules in interphase cells and development of abnormal spindles and chromosome distribution in mitotic cells. Although these effects are very similar to the cellular alterations caused by vinblastine, LU103793 does not inhibit vinblastine binding to unpolymerized tubulin in vitro. Our results suggest that LU103793 exerts its cytotoxic activity primarily through disruption of microtubule organization.
de Arruda
M
M
BASF Bioresearch Corporation, Worcester, Massachusetts 01605-4314, USA.
Cocchiaro
C A
CA
Nelson
C M
CM
Grinnell
C M
CM
Janssen
B
B
Haupt
A
A
Barlozzari
T
T
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002877:Chromosomes, Human / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004347:Drug Interactions; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D009842:Oligopeptides; D014404:Tubulin; D014747:Vinblastine; C094621:cemadotin; D006160:Guanosine Triphosphate