Screen of Approved Drugs Turns Up Anti-Melanoma Agent

Anti-cancer drug developers have found that the drug mebendazole, a commonly used treatment for worm infections in domesticated animals, has potent activity against human malignant melanoma cells.

Investigators at the New York University School of Medicine (New York City, USA) chose to screen already approved drugs rather than start from scratch in their effort to find a chemotherapeutic agent for metastatic melanoma, a disease that fails to respond to available therapies.

They screened 2,000 compounds from the Spectrum Library of approved drugs at a concentration of 1 µmol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line.

They reported in the July 30, 2008, online edition of the journal Molecular Cancer Research that they had identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Four of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) were benzimidazoles, a class of structurally related, tubulin-disrupting drugs.

Mebendazole was selected for further study based on its favorable pharmacokinetic profile. The data revealed that mebendazole inhibited melanoma growth and preferentially induced apoptosis in melanoma cells compared with melanocytes. The phosphorylation of Bcl-2 protein, which occurred rapidly after treatment with mebendazole in melanoma cells but not in melanocytes, mediated the apoptotic response. Phosphorylation of Bcl-2 in melanoma cells prevented its interaction with pro-apoptotic Bax, thereby promoting apoptosis.

"While rational drug design remains a perfectly valid way to develop cancer therapies, we also need approaches that are less costly and more productive of new effective treatments,” said senior author Dr. Seth J. Orlow, professor of dermatology at the New York University School of Medicine. "You could say this is more of a guerrilla approach. Instead of screening millions of untested compounds for an agent that inhibits or stimulates a particular molecular target, we chose to screen a large library of already approved drugs for novel activity against melanoma cells, and then advance the most promising candidate rapidly to clinical practice. We are now focused on determining the range of doses to be tested in the clinic, whether specific types of melanomas will respond better than others, and whether combining mebendazole with other agents will be of further benefit.”

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