Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Abstract

Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

“…For instance, we recently used a similar approach to overcome arsenic trioxide resistance in melanoma cells (20). A chemical genetics approach has also been used successfully to identify benzimidazoles, a class of structurally related, tubulin-disrupting drugs, as agents preferentially toxic to melanoma cells compared with melanocytes (21). In addition, this approach could be used to reveal additional novel mechanisms and targets for cancer treatment.…”

“…We have previously used this screening methodology to identify novel compounds and targets involved in the regulation of mammalian pigmentation (16)(17)(18)(19), in the evasion of arsenic trioxide resistance in melanoma cells (20), and in the identification of agents specifically cytotoxic to melanoma (21).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Oral administration of mebendazole in mice elicited a strong antitumor effect in a subcutaneous model and reduced lesions in experimentally induced lung metastasis without any toxicity when compared with paclitaxel-treated mice [9,20]. Furthermore, the drug induced a dose-and time-dependent apoptotic response in chemoresistant melanoma cells via inactivation of Bcl-2 [21]. Mebendazole inhibited melanoma growth with an average IC50 of 0.32 µM and preferentially induced apoptosis in melanoma cells compared with melanocytes.…”

“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”

“…For the anticancer activity of mebendazole impairment of the organization of tubulin was identified as main intracellular effect in lung cancer, gastric cancer, leukemia and brain tumors [9,20,22,25,32]. Cytotoxicity was enhanced by alterations of the regulators of apoptosis, such as Bcl2/XIAP, in melanoma, lung cancer and adrenocortical carcinoma [9,19,21,67]. In human cells, mebendazole suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation [27].…”