Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, People's Republic of China.
Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People's Republic of China.
Cancer Chemother Pharmacol. 2018 Sep;82(3):383-394. doi: 10.1007/s00280-018-3627-3. Epub 2018 Jun 16.
Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer.
MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model.
The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone.
The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.
紫杉醇为基础的放化疗已被证明在治疗晚期食管癌患者中是有效的。然而，其毒性和耐药性的发展限制了其抗癌效率。本研究旨在评估拉帕替尼（一种表皮生长因子受体（EGFR）和人表皮生长因子受体 2（HER2）的双重酪氨酸抑制剂）与紫杉醇联合应用于食管鳞癌的抗肿瘤作用。
MTT 法评估拉帕替尼与紫杉醇联合对食管鳞癌细胞系（KYSE150、KYSE450、KYSE510 和 TE-7）生长的影响。通过划痕愈合试验、Transwell 试验和 Annexin V-FITC/PI 染色试验测定两种药物联合对细胞侵袭、迁移和凋亡的活性。Western blot 试验分析两种药物对 EGFR/HER2 信号通路的影响。在 KYSE450 异种移植裸鼠模型中评估体内疗效。
拉帕替尼与紫杉醇联合具有高度协同抑制细胞生长作用，合并指数<1，并显著抑制食管鳞癌细胞的侵袭和迁移能力。食管鳞癌细胞经拉帕替尼加紫杉醇处理后凋亡率增加。暴露于拉帕替尼和紫杉醇后，磷酸化 EGFR 和 HER2 以及下游分子 MAPKs 和 AKT 的激活显著降低。体内研究表明，两种药物联合具有比单一药物更强的抗肿瘤疗效。
拉帕替尼与紫杉醇联合具有协同抗肿瘤活性，提示其在治疗食管鳞癌患者中的潜在应用价值。
