Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Oxid Med Cell Longev. 2019 May 7;2019:6342104. doi: 10.1155/2019/6342104. eCollection 2019.
Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.
肺癌是全球癌症死亡的主要原因，五年生存率低于 30%。在疾病初期，临床有效的化疗治疗方法最终可能会因为耐药性而面临无药可用的困境；因此，寻找新的有效的肺癌治疗药物是一个必要且重要的问题。能够进一步增加癌细胞氧化应激的化合物被认为具有抗癌潜力，因为它们具有诱导细胞凋亡的能力。本研究主要通过调节线粒体活性氧（mtROS）和氧化磷酸化（OXPHOS）来研究海洋海绵甾体类化合物 BA6（异海松烷）对肺癌细胞凋亡的影响。BA6 对多种癌细胞系具有细胞毒性作用，但对非肿瘤细胞没有影响。BA6 处理的肺癌细胞中细胞 ROS 和 mtROS 均显著增加，进而导致线粒体膜电位（MMP）丧失。BA6 处理的肺癌细胞中氧化应激的增加伴随着抗氧化酶 Cu/Zn SOD、MnSOD 和过氧化氢酶表达的减少。此外，线粒体中的 OXPHOS 和细胞质中的糖酵解均受到抑制，从而降低下游 ATP 的产生。线粒体靶向抗氧化剂 MitoTEMPO 的预处理通过线粒体依赖性凋亡途径减少了 BA6 诱导的细胞凋亡，其伴随细胞活力增加、mtROS 减少、MMP 增强以及 cleaved caspase-3 和 caspase-9 蛋白表达抑制。总之，本研究结果阐明了 BA6 通过线粒体凋亡途径诱导肺癌细胞凋亡的机制，表明它是治疗人类肺癌的一种潜在创新替代方法。
