Abstract
9075 Background: Defects in apoptosis are thought to contribute to melanoma chemoresistance, making the anti-apoptotic protein Bcl-2 an attractive therapeutic target. We identified mebendazole (MBZ), a microtubule binding agent, as an inducer of melanoma cytotoxicity via a Bcl-2 dependent mechanism in vitro (Mol Cancer Res, Aug 2008). In the present study, we assessed the effect of MBZ on human melanoma tumor growth and progression in a mouse xenograft model and compared the ability of MBZ to inhibit growth of cultured melanoma cells to that of oblimersen (OBL), an antisense drug targeting Bcl-2. Methods: Growth of human M-14 melanoma xenografts in mice administered MBZ orally at doses from 0.1 to 2 mg were compared to tumor growth in mice receiving 100mg/kg intraperitoneal temozolomide (TMZ) or vehicle alone. Tumor diameter, volume, histopathology, and immunohistochemical staining of caspase 3 and Ki67 were assessed. Bcl-2 phosphorylation was determined by immunoblotting. MBZ and OBL-induced melanoma growth inhibition was analyzed by MTT assay. Results: Anti-melanoma effects of MBZ were dose- dependent up to 1 mg which displayed a 72% reduction in tumor volume compared to vehicle treated mice. This reduction in volume was accompanied by a 46% decrease in proliferating cells and an 81% increase in apoptotic cells. Moreover, 1 mg MBZ inhibited tumor growth as effectively as high dose TMZ, the current melanoma standard of care. Orally administered MBZ treatment resulted in Bcl-2 phosphorylation in vivo, further confirming its mechanism of action. MBZ inhibited growth of melanoma cells in culture more effectively than OBL with GI50 values of 0.32 uM and 7.45 uM, respectively. Conclusions: MBZ safely and effectively inhibits melanoma growth and progression in a xenograft model. A phase II clinical trial investigating MBZ's utility as adjuvant therapy in patients with stage IV, resected melanoma is planned. No significant financial relationships to disclose.
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