Currently, combination therapy is considered the most effective solution for a selective chemotherapeutic effect in the treatment of colon cancer. This study investigated the death of both colon cancer HT29 cells and healthy vascular smooth muscle TG-Ha-VSMC cells (VSMCs) induced by naringin combined with endoplasmic reticulum (ER) stress and NF-κB inhibition. Naringin combined with tunicamycin and BAY 11-7082 suppressed the proliferation of HT29 cells in a dose-dependent manner and induced particularly apoptotic death without significantly affecting healthy VSMCs according to Annexin V/PI staining and AO/EB staining analyses. Insufficient antioxidant defense and heat shock response as well as excessive ROS generation were observed in HT29 cells following combination therapy. Quantitative real-time PCR and western blot analysis demonstrated that drug combination-induced mitochondrial apoptosis was activated through the ROS-mediated PERK/eIF2α/ATF4/CHOP pathway. Additionally, naringin combination significantly reduced the sXBP expression induced by tunicamycin+BAY 11-7082 in a dose-dependent manner. In conclusion, this study found that naringin combined with tunicamycin+BAY 11-7082 efficiently induced apoptotic cell death in HT29 colon cancer cells via oxidative stress and the PERK/eIF2α/ATF4/CHOP pathway, suggesting that naringin combined with tunicamycin plus BAY 11-7082 could be a new combination therapy strategy for effective colon cancer treatment with minimal side effects on healthy cells.

当前，组合疗法被认为是治疗结肠癌的选择性化学疗法效果的最有效解决方案。这项研究调查了柚皮苷联合内质网（ER）应激和NF-κB抑制作用诱导的结肠癌HT29细胞和健康血管平滑肌TG-Ha-VSMC细胞（VSMC）的死亡。根据膜联蛋白V / PI染色和AO / EB染色分析，柚皮苷与衣霉素和BAY 11-7082联合以剂量依赖性方式抑制HT29细胞的增殖，并诱导凋亡的死亡，而不会显着影响健康的VSMC。联合治疗后，在HT29细胞中观察到抗氧化剂防御和热休克反应不足，以及过多的ROS生成。实时定量PCR和蛋白质印迹分析表明，药物组合诱导的线粒体凋亡通过ROS介导的PERK /eIF2α/ ATF4 / CHOP途径被激活。另外，柚皮苷组合以剂量依赖性方式显着降低衣霉素+ BAY 11-7082诱导的sXBP表达。总之，这项研究发现，柚皮苷联合衣霉素+ BAY 11-7082通过氧化应激和PERK /eIF2α/ ATF4 / CHOP途径有效诱导HT29结肠癌细胞凋亡，提示柚皮苷联合衣霉素+ BAY 11- 7082可能是一种新的联合治疗策略，可有效治疗结肠癌，且对健康细胞的副作用极小。另外，柚皮苷组合以剂量依赖性方式显着降低衣霉素+ BAY 11-7082诱导的sXBP表达。总之，这项研究发现，柚皮苷联合衣霉素+ BAY 11-7082通过氧化应激和PERK /eIF2α/ ATF4 / CHOP途径有效诱导HT29结肠癌细胞凋亡，提示柚皮苷联合衣霉素+ BAY 11- 7082可能是一种新的联合治疗策略，可有效治疗结肠癌，且对健康细胞的副作用极小。另外，柚皮苷组合以剂量依赖性方式显着降低衣霉素+ BAY 11-7082诱导的sXBP表达。总之，这项研究发现，柚皮苷联合衣霉素+ BAY 11-7082通过氧化应激和PERK /eIF2α/ ATF4 / CHOP途径有效诱导HT29结肠癌细胞凋亡，提示柚皮苷联合衣霉素+ BAY 11- 7082可能是一种新的联合治疗策略，可有效治疗结肠癌，且对健康细胞的副作用极小。