Trastuzumab and oxaliplatin exhibit a synergistic antitumor effect in HER2-postive gastric cancer cells
Trastuzumab and oxaliplatin exhibit a synergistic antitumor effect in HER2-postive gastric cancer cells
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曲妥珠单抗和奥沙利铂在 HER2 阳性胃癌细胞中表现出协同抗肿瘤作用
DOI：
10.1097/cad.0000000000000048
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发表时间：
2014-03-01
影响因子：
2.3
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
--
作者：
Ding, Xiaodi;Qu, Xiujuan;Liu, Yunpeng
最近推荐曲妥珠单抗联合卡培他滨/顺铂 (XP) 与持续输注 5-氟尿嘧啶/顺铂 (FP) 方案治疗表皮生长因子受体 2 (HER2) 阳性晚期胃癌。然而，目前尚不清楚曲妥珠单抗与其他化疗方案联合应用在临床中是否合理。我们的研究表明，在常用的第三代铂衍生物奥沙利铂中添加曲妥珠单抗可增强体外抗肿瘤作用。在 MTT 测定中，奥沙利铂和曲妥珠单抗联合治疗显着降低了在 HER2 阳性胃癌细胞中诱导 50% 生长抑制所需的奥沙利铂浓度。进一步研究表明，曲妥珠单抗-奥沙利铂组合可诱导细胞周期停滞并降低 p-AKT 和 p-ERK 的表达。值得注意的是，这种治疗组合诱导了切除修复交叉互补组 1 (ERCC1) 蛋白的下调，该蛋白在蛋白水平上参与奥沙利铂-DNA 铂加合物的关键修复过程。在 HER2 阳性乳腺癌细胞中也观察到类似的变化。这些发现表明曲妥珠单抗可协同奥沙利铂对 HER2 阳性胃癌和乳腺癌细胞的细胞毒作用。我们的研究为优化该联合方案治疗 HER2 阳性胃癌患者提供了临床前证据。
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.