Influence of fatty acid synthase inhibitor orlistat on the DNA repair enzyme O6-methylguanine-DNA methyltransferase in human normal or malignant cells in vitro

摘要: Tetrahydrolipstatin (orlistat), an inhibitor of lipases and fatty acid synthase, is used orally for long-term treatment obesity. Although the drug possesses striking antitumor activities in vitro against human cancer cells vivo animal tumors, it also induces precancerous lesions rat colon. Therefore, we tested effect orlistat on expression O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that plays essential role control mutagenesis carcinogenesis. Western blot analysis demonstrated 2-day continuous exposure to 40 µM did not affect MGMT levels melanoma cell line, but downregulated protein by 30-70% peripheral blood mononuclear cells, two leukemia colon lines. On other hand, alter noticeably mRNA expression. Differently from lomeguatrib (a false substrate, strong MGMT) reduce substantially function after 2-h target agent, suggesting this competitive protein. Combined with showed additive reduction levels. More importantly, orlistat-mediated downregulation was markedly amplified when combined methylating agent endowed carcinogenic properties such as temozolomide. In conclusion, even if scarcely absorbed oral route, possible could local MGMT-mediated protection damage provoked compounds gastrointestinal tract epithelial thus favoring chemical