Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model.
Inheritance of a gene mutation leads to the initiation of 5 to 10% of most cancers, including colon cancer cases. We developed a chemoprevention strategy using a novel combination of the non-steroidal anti-inflammatory (NSAID) sulindac plus the anthelminthic benzimidazole, mebendazole. This oral drug combination was effective in the ApcMin/+ mouse model of Familial Adenomatous Polyposis (FAP). Treatment with 35 mg/kg daily mebendazole reduced the number of intestinal adenomas by 56% (P = 0.0002), 160 ppm sulindac by 74% (P < 0.0001), and the combination by 90% (P < 0.0001). The combination significantly reduced microadenomas, polyp number and size in both the small intestines and colon when compared to untreated controls or sulindac alone. Mebendazole as a single agent decreased COX2 expression, blood vessel formation, VEGFR2 phosphorylation, and worked synergistically with sulindac to reduce overexpression of MYC, BCL2, and various pro-inflammatory cytokines. Given the low toxicity of mebendazole, these preclinical findings support the consideration of clinical trials for high risk cancer patients using mebendazole either alone or in combination. The findings have implications for populations with moderate and above risk for developing cancer.
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Tara
T
Williamson
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ren-Yuan
RY
Bai
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Verena
V
Staedtke
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
David
D
Huso
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Gregory J
GJ
Riggins
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D008297:Male; D008463:Mebendazole / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013467:Sulindac / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013467:Sulindac; D008463:Mebendazole
APC; FAP; colon cancer; mebendazole; sulindac