Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Environ Toxicol. 2018 Nov;33(11):1153-1159. doi: 10.1002/tox.22621. Epub 2018 Aug 23.
Epidermal growth factor receptor (EGFR) mutations have been identified in approximately 55% of lung cancer patients in Taiwan. Gefitinib (Iressa) and Erlotinib (Tarceva) are the first-generation targeting drugs to patients with EGFR gene mutants a work by inhibiting tyrosine kinase activity. However, resistance in EGFR-mutated patients to first-generation tyrosine kinase inhibitor (TKI) therapy after 8-11 months of treatment has occurred. Betulinic acid (BetA) is a pentacyclic triterpenoid natural product derived from widespread plants. BetA has been reported to have a cytotoxic effect in several cancers. The purpose of this study is to investigate the effects and mechanisms of BetA on dampening EGFR TKI-resistance of lung cancer cells. Our study has demonstrated by MTT assay that combining BetA and an EGFR TKI increased the cytotoxicity against EGFR TKI-resistance lung cancer cells. Based on flow cytometry, combination treatments of BetA with an EGFR TKI enhanced Sub-G1 accumulation, induced apoptosis and induced mitochondrial membrane potential loss. Using western blotting, BetA and EGFR TKI combined treatments inhibited cell cycle related protein and triggered apoptosis- and autophagy- related protein expression. Taken together, our data suggests that a target therapy combining BetA with an EGFR TKI improves drug efficacy in EGFR TKI-resistant lung cancer cells.
表皮生长因子受体（EGFR）突变在台湾约 55%的肺癌患者中被发现。吉非替尼（Iressa）和厄洛替尼（Tarceva）是第一代针对 EGFR 基因突变患者的靶向药物，通过抑制酪氨酸激酶活性发挥作用。然而，在 EGFR 突变型患者中，第一代酪氨酸激酶抑制剂（TKI）治疗 8-11 个月后会出现耐药性。白桦脂酸（BetA）是一种来源于广泛植物的五环三萜天然产物。有报道称，BetA 在几种癌症中具有细胞毒性作用。本研究旨在探讨 BetA 对肺癌细胞 EGFR TKI 耐药性的影响及其机制。我们的研究通过 MTT 检测表明，BetA 与 EGFR TKI 联合使用可增加对 EGFR TKI 耐药性肺癌细胞的细胞毒性。基于流式细胞术，BetA 与 EGFR TKI 的联合治疗增强了 Sub-G1 积累，诱导了细胞凋亡并诱导了线粒体膜电位丧失。通过 Western blot，BetA 和 EGFR TKI 的联合治疗抑制了细胞周期相关蛋白，并触发了细胞凋亡和自噬相关蛋白的表达。总之，我们的数据表明，将 BetA 与 EGFR TKI 联合进行靶向治疗可提高 EGFR TKI 耐药性肺癌细胞的药物疗效。
