title: Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53.
abstract: Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF-κB and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-κB. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-κB. These findings support the link between NF-κB and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.
authors.affiliation: Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland E-mail : zychan@biol.uni.lodz.pl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Rogalska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sliwinska
authors.forename: Jacek
authors.initials: J
authors.lastname: Kasznicki
authors.forename: Jozef
authors.initials: J
authors.lastname: Drzewoski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Marczak
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D003609:Dactinomycin / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D034261:Epothilones / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D034261:Epothilones; D007004:Hypoglycemic Agents; D016328:NF-kappa B; C514113:Po-Pro-1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; C093787:epothilone A; C025942:7-aminoactinomycin D; D008687:Metformin; D000068900:Sitagliptin Phosphate