title: BM6, a new semi-synthetic vinca alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles.
abstract: The aim of this study was to evaluate the anti-tumor activities and to establish the mechanism of the action of 3-decarboxyl-acetyloxylmethyl-anhydrovinblastine (BM6), a new semi-synthetic Vinca alkaloid, in an effort towards finding the favorable therapeutics of Vinca alkaloid derivatives. BM6 was characterized by its superior in vivo activity to vinorelbine in preclinical tumor models, though BM6 exerted in vitro cytotoxic activity against a wide spectrum of tumor cell lines with IC(50) values generally 10-fold higher than the classic Vinca alkaloids. Of note, BM6 displayed more potent cytotoxic activity against multidrug-resistant sublines. We further found that BM6 shared the mitotic arresting and tubulin-interacting properties comparable with other Vinca alkaloids. BM6 also induced significant cell cycle arrested in mitosis and cytoskeleton disruption via interacting with the Vinca binding site on tubulin. Encouragingly, the features in term of its higher tubulin binding affinities and better pharmacokinetic profiles highlight BM6 distinct from other Vinca alkaloids, which help provide more data for exploiting new semi-synthetic Vinca alkaloids.
authors: Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
authors: Weihong
authors: W
authors: Li
authors: Yong
authors: Y
authors: Shao
authors: Lihong
authors: L
authors: Hu
authors: Xiongwen
authors: X
authors: Zhang
authors: Yi
authors: Y
authors: Chen
authors: Linjiang
authors: L
authors: Tong
authors: Chuan
authors: C
authors: Li
authors: Xu
authors: X
authors: Shen
authors: Jian
authors: J
authors: Ding
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D011485:Protein Binding; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D014750:Vincristine; D014747:Vinblastine; D000077235:Vinorelbine