Oncocidin A1: a novel tubulin-binding drug with antitumor activity against human breast and ovarian carcinoma xenografts in nude mice.
We identified a structural analog of thyroid hormone, methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (Oncocidin A1), that inhibits human carcinoma cell proliferation and the growth of human breast (MDA MB-231) and ovarian (OVCAR-3) carcinoma xenografts in nude mice. This novel antitumor agent is orally bioavailable and well tolerated by animals. Exposure of MCF-7 and MDA MB-231 breast carcinoma cells to Oncocidin A1 in vitro caused a cell-cycle arrest in prometaphase (a G2/M arrest) and apoptosis, suggesting a cytotoxic mechanism involving mitotic spindle function. The interaction of Oncocidin A1 with microtubules was demonstrated by: 1) immunofluorescence studies of microtubule assembly in the presence of the drug in cell-free and in cellular assays; and 2) in vitro binding inhibition studies involving radiolabeled Oncocidin A1 or colchicine and tubulin monomers. Taken together, these experiments indicate that Oncocidin A1 perturbs cellular microtubule assembly, possibly by binding to the colchicine site on tubulin. Three-dimensional structural modelling of Oncocidin A1 revealed that it can adopt a twisted conformation similar to that of combretastatin A-4, which binds to the colchicine site of tubulin. The novel structural features of Oncocidin A1 could guide the design of a new class of microtubule-binding antitumor agents having substantially reduced normal tissue toxicity upon oral administration.
Pharmaceutical Discovery Division, SRI International, Menlo Park, CA 94025, USA. xiaoying_chen@qm.sri.com
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D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006801:Humans; D007463:Iodobenzoates / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008677:Metaphase / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011485:Protein Binding; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D007463:Iodobenzoates; D010647:Phenyl Ethers; D014404:Tubulin; C436733:methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate