The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells.
Microtubules have a critical role in cell division, and consequently various microtubule inhibitors have been developed as anticancer drugs. In this study, we assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a potent antitumor property both in vitro and in vivo. Treatment of lung cancer cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release. MZ induces abnormal spindle formation in mitotic cancer cells and enhances the depolymerization of tubulin, but the efficacy of depolymerization by MZ is lower than that by nocodazole. Oral administration of MZ in mice elicited a strong antitumor effect in a s.c. model and reduced lung colonies in experimentally induced lung metastasis without any toxicity when compared with paclitaxel-treated mice. We speculate that tumor cells may be defective in one mitotic checkpoint function and sensitive to the spindle inhibitor MZ. Abnormal spindle formation may be the key factor determining whether a cell undergoes apoptosis, whereas strong microtubule inhibitors elicit toxicity even in normal cells.
Sasaki
Ji-ichiro
J
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Ramesh
Rajagopal
R
Chada
Sunil
S
Gomyo
Yoshihito
Y
Roth
Jack A
JA
Mukhopadhyay
Tapas
T
D000284:Administration, Oral; D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008463:Mebendazole / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects*; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000969:Antinematodal Agents; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D003574:Cytochrome c Group; D014404:Tubulin; D008463:Mebendazole; D020169:Caspases; D017239:Paclitaxel