XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts

Doudican, Nicole, Byron, Sara A., Pollock, Pamela M., & Orlow, Seth (2013) XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts. Anticancer Drugs, 24(2), pp. 181-188.

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Mebendazole (MBZ) was identified as a promising therapeutic on the basis of its ability to induce apoptosis in melanoma cell lines through a B-cell lymphoma 2 (BCL2)-dependent mechanism. We now show that in a human xenograft melanoma model, oral MBZ is as effective as the current standard of care temozolomide in reducing tumor growth. Inhibition of melanoma growth in vivo is accompanied by phosphorylation of BCL2 and decreased levels of X-linked inhibitor of apoptosis (XIAP). Reduced expression of XIAP on treatment with MBZ is partially mediated by its proteasomal degradation. Furthermore, exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating XIAP's inhibition on apoptosis. XIAP expression on exposure to MBZ is indicative of sensitivity to MBZ as MBZ-resistant cells do not show reduced levels of XIAP after treatment. Resistance to MBZ can be reversed partially by siRNA knockdown of cellular levels of XIAP. Our data indicate that MBZ is a promising antimelanoma agent on the basis of its effects on key antiapoptotic proteins.

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ID Code: 54897
Item Type: Journal Article
Refereed: Yes
Keywords: melanoma, mebendazole, XIAP, therapeutic, BCL2
DOI: 10.1097/CAD.0b013e32835a43f1
ISSN: 1473-5741
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 Lippincott Williams & Wilkins
Deposited On: 20 Dec 2012 06:31
Last Modified: 02 Feb 2014 05:53

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