The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma.

Abstract

On-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we conducted chemical screens and identified the antihelmintic flubendazole. Flubendazole induced cell death in leukemia and myeloma cell lines and primary patient samples at nanomolar concentrations. Moreover, it delayed tumor growth in leukemia and myeloma xenografts without evidence of toxicity. Mechanistically, flubendazole inhibited tubulin polymerization by binding tubulin at a site distinct from vinblastine. In addition, cells resistant to vinblastine because of overexpression of P-glycoprotein remained fully sensitive to flubendazole, indicating that flubendazole can overcome some forms of vinblastine resistance. Given the different mechanisms of action, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. Flubendazole synergized with vinblastine to reduce the viability of OCI-AML2 cells. In addition, combinations of flubendazole with vinblastine or vincristine in a leukemia xenograft model delayed tumor growth more than either drug alone. Therefore, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma.

• Authors: Paul A Spagnuolo, Jiayi Hu, Rose Hurren, Xiaoming Wang, Marcela Gronda, Mahadeo A Sukhai, Ashley Di Meo, Jonathan Boss, Iman Ashali, Reza Beheshti Zavareh, Noah Fine, Craig D Simpson, Sumaiya Sharmeen, Rob Rottapel, Aaron D Schimmer
• Journal: Blood (Blood) Vol. 115 Issue 23 Pg. 4824-33 (Jun 10 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20348394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antinematodal Agents
• Antineoplastic Agents, Phytogenic
• Vinca Alkaloids
• Vinblastine
• Mebendazole
• flubendazole

Topics

• Animals
• Antinematodal Agents (agonists, pharmacology, therapeutic use)
• Antineoplastic Agents, Phytogenic (agonists, pharmacology, therapeutic use)
• Cell Death
• Cell Survival
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• HeLa Cells
• Humans
• Leukemia (drug therapy, metabolism)
• Male
• Mebendazole (agonists, analogs & derivatives, pharmacology, therapeutic use)
• Mice
• Microtubules (metabolism)
• Multiple Myeloma (drug therapy, metabolism)
• U937 Cells
• Vinblastine (agonists, pharmacology, therapeutic use)
• Vinca Alkaloids (pharmacology)
• Xenograft Model Antitumor Assays (methods)