title: Trastuzumab and oxaliplatin exhibit a synergistic antitumor effect in HER2-postive gastric cancer cells.
abstract: Trastuzumab has recently been recommended for the treatment of epidermal growth factor receptor-2 (HER2)-positive advanced gastric cancer in combination with the capecitabine/cisplatin (XP) versus continuous infusion of 5-fluorouracil/cisplatin (FP) regimen. However, it is unclear whether it is rational to combine trastuzumab with other chemotherapy regimens in clinical practice. Our study demonstrates that adding trastuzumab to oxaliplatin, a commonly used third-generation platinum derivative, increases the antitumor effect in vitro. In MTT assays, combination treatment with oxaliplatin and trastuzumab significantly decreased the concentration of oxaliplatin required to induce 50% growth inhibition in HER2-positive gastric cancer cells. Further investigation revealed that the trastuzumab-oxaliplatin combination induced cell cycle arrest and decreased expression of both p-AKT and p-ERK. Notably, this treatment combination induced downregulation of the excision repair cross-complementation group 1 (ERCC1) protein, which is involved in the key repair process of the oxaliplatin-DNA platinum adduct at the protein level. Similar changes were also observed in HER2-positive breast cancer cells. These findings suggest that trastuzumab synergizes the cytotoxic effect of oxaliplatin on HER2-positive gastric and breast cancer cells. Our study provides preclinical evidence for the optimization of this combination regimen in the treatment of HER2-positive gastric cancer patients.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Ding
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Yibo
authors.initials: Y
authors.lastname: Fan
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Che
authors.forename: Jinglei
authors.initials: J
authors.lastname: Qu
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004720:Endonucleases; D051549:Glutathione S-Transferase pi; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C071447:ERCC1 protein, human