title: Combination of gefitinib and DNA methylation inhibitor decitabine exerts synergistic anti-cancer activity in colon cancer cells.
abstract: Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Yun-feng
authors.initials: YF
authors.lastname: Lou
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
authors.forename: Zheng-zhi
authors.initials: ZZ
authors.lastname: Zou
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Pin-jia
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Affiliated Donghua Hospital of Sun Yat-sen University, Dongguan, China.
authors.forename: Guo-bin
authors.initials: GB
authors.lastname: Huang
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The Affiliated Donghua Hospital of Sun Yat-sen University, Dongguan, China.
authors.forename: De-qing
authors.initials: DQ
authors.lastname: Zheng
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xiu-rong
authors.initials: XR
authors.lastname: Yu
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xiao-yong
authors.initials: XY
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C417551:XAF1 protein, human; D000077209:Decitabine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D001374:Azacitidine; D000077156:Gefitinib