title: Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines.
abstract: Hypoxia is recognized as an important factor contributing to cancer development and drug resistance. Cetuximab, a chimeric monoclonal antibody to EGFR, is known to inhibit HIF-1 alpha expression levels and to enhance the cytotoxicity of chemotherapeutic agents. We demonstrated that hypoxia induced drug resistance in gastric cancer cells. Cetuximab enhanced oxaliplatin-induced cytotoxicity and apoptosis in normoxia and caused a reversal of drug resistance in hypoxia. Normoxic and hypoxic gastric cancer cells were treated with cetuximab, oxaliplatin or the combination and assessed for cell growth, proliferation, and apoptosis. Combination treatment resulted in a marked inhibition of HIF-1 alpha expression levels in hypoxic cells and caused a significant reduction in the expression of activated phosphorylated AKT, ERK1/2, p-BAD and VEGF in both normoxia and hypoxia with greater levels of inhibition in hypoxia. In summary, cetuximab inhibits HIF-1 alpha expression via the MAPK/ERK and PI3K/AKT signaling pathways and functions to overcome drug resistance induced by hypoxia. Cetuximab-oxaliplatin combination therapy may therefore emerge as an attractive treatment strategy for advanced gastric cancer.
authors.affiliation: State Key Laboratory of Oncology in Southern China and Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, PR China.
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Shi
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Chen
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Miao-Zhen
authors.initials: MZ
authors.lastname: Qiu
authors.forename: Fang-Hua
authors.initials: FH
authors.lastname: Li
authors.forename: Shu-Li
authors.initials: SL
authors.lastname: Yan
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000068818:Cetuximab; D004347:Drug Interactions; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000068818:Cetuximab