Li Hui, Jiao Shun, Li Xin, Banu Hasina, Hamal Shreejana, Wang Xianrong
a Department of Obstetrics and Gynaecology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), The Second Clinical Medical College, Yangtze University, Jing Zhou, People's Republic of China.
b Department of Obstetrics and Gynaecology, RenMin Hospital of Wuhan University, Wuhan, People's Republic of China.
Can J Physiol Pharmacol. 2017 Jan;95(1):43-50. doi: 10.1139/cjpp-2016-0124. Epub 2016 Aug 11.
Targeting mitochondria is an attractive strategy for cancer therapy due to the essential roles of mitochondria in cancer cell energy metabolism. In this study, we show that mefloquine, an antibiotic drug, effectively targets cervical cancer cells through impairing mitochondrial function. Mefloquine dose-dependently induces apoptosis and inhibits proliferation and anchorage-independent colony formation of multiple cervical cancer cell lines. Mefloquine alone inhibits cervical tumor growth in vivo and its combination with paclitaxel is synergistic in inhibiting tumor growth. Mechanistically, mefloquine inhibits mitochondrial function via inhibiting mitochondrial respiration, decreasing membrane potential, increasing ROS generation, and decreasing ATP level. We further show that mefloquine suppresses activation of mTOR signaling pathway in HeLa cells. However, the inhibitory effects of mefloquine on survival, colony formation, and ATP are abolished in mitochondrial respiration-deficient HeLa ρ cells, demonstrating that mefloquine acts on cervical cancer cells via targeting mitochondrial respiration. Inhibition of mTOR signaling pathway by mefloquine was also reversed in HeLa ρ cells, suggesting deactivation of mTOR pathway as a consequence of mitochondria function disruption. Our work suggests that mefloquine is a potential candidate for cervical cancer treatment. Our work also highlights the therapeutic value of anti-mitochondria and establishes the association of mitochondrial function and the activation of mTOR signaling pathway in cervical cancer cells.
由于线粒体在癌细胞能量代谢中发挥着重要作用，靶向线粒体是一种颇具吸引力的癌症治疗策略。在本研究中，我们发现抗生素药物甲氟喹可通过损害线粒体功能有效靶向宫颈癌细胞。甲氟喹剂量依赖性地诱导多种宫颈癌细胞系凋亡，并抑制其增殖和非锚定依赖性集落形成。单独使用甲氟喹可在体内抑制宫颈肿瘤生长，且其与紫杉醇联合使用对肿瘤生长具有协同抑制作用。从机制上来说，甲氟喹通过抑制线粒体呼吸、降低膜电位、增加活性氧生成及降低ATP水平来抑制线粒体功能。我们进一步表明，甲氟喹可抑制HeLa细胞中mTOR信号通路的激活。然而，在缺乏线粒体呼吸功能的HeLa ρ细胞中，甲氟喹对细胞存活、集落形成及ATP的抑制作用消失，这表明甲氟喹通过靶向线粒体呼吸作用于宫颈癌细胞。在HeLa ρ细胞中，甲氟喹对mTOR信号通路的抑制作用也被逆转，提示mTOR通路失活是线粒体功能破坏的结果。我们的研究表明，甲氟喹是宫颈癌治疗的潜在候选药物。我们的工作还突出了抗线粒体治疗的价值，并确立了线粒体功能与宫颈癌细胞中mTOR信号通路激活之间的关联。
