Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole.
OBJECTIVE
Clotrimazole, an imidazole derivative and inhibitor of cytochrome P-450, inhibits the proliferation of cancer cells by downregulating the movement of intracellular Ca++ and K+ and by interfering with the translation initiation process. Clotrimazole inhibits the proliferation of human glioblastoma multiforme cells; it induces morphological changes toward differentiation and blocks the cell cycle in the G1/G1 phase. In vitro, clotrimazole enhances the antitumor effect of cisplatin by inducing wild-type p53-mediated apoptosis. The authors examined the effect of clotrimazole on tumor growth, sensitivity to cisplatin, and survival of rats with intracranial gliomas.


METHODS
Cultured C6 and 9L glioma cells were exposed to clotrimazole, and cell growth was assessed using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide colorimetric assay. Clotrimazole produced a dose- and time-dependent inhibition of cell proliferation. The growth inhibitory effect of clotrimazole could not be overcome by exogenous stimulation with epidermal growth factor. Both C6 and 9L glioma cells were implanted into the rat brain and after 5 days, the animals were treated with a daily single dose of clotrimazole for 8 consecutive days. Clotrimazole treatment caused a significant inhibition of intracranial tumor growth. The survival of rats with 9L gliomas was analyzed after 10 days of treatment with clotrimazole, cisplatin, or a combination of clotrimazole and cisplatin. Rats treated with either drug displayed a significantly prolonged survival time; however, the combination treatment resulted only in an additional survival benefit.


CONCLUSIONS
Clotrimazole effectively inhibits cell proliferation and tumor growth, and prolongs survival of rats with intracranial gliomas. Clotrimazole may be considered a potential anticancer drug for treatment of intracranial gliomas.
Khalid
M Humayun
MH
Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, DC 20059, USA. humayunkhalid@hotmail.com
Tokunaga
Yoshiharu
Y
Caputy
Anthony J
AJ
Walters
Eric
E
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000401:mortality* / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D003022:Clotrimazole / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005910:Glioma / Q000401:mortality* / Q000473:pathology*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D003022:Clotrimazole; D002945:Cisplatin