Therapeutic effects of antibiotic drug mefloquine against cervical cancer through impairing mitochondrial function and inhibiting mTOR pathway.
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 ρ0cells, demonstrating that mefloquine acts on cervical cancer cells via targeting mitochondrial respiration. Inhibition of mTOR signaling pathway by mefloquine was also reversed in HeLa ρ0cells, 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.
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.
Hui
H
Li
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.
Shun
S
Jiao
b Department of Obstetrics and Gynaecology, RenMin Hospital of Wuhan University, Wuhan, People's Republic of China.
Xin
X
Li
c Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou, People's Republic of China.
Hasina
H
Banu
c Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou, People's Republic of China.
Shreejana
S
Hamal
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.
Xianrong
X
Wang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology* / Q000627:therapeutic use*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D015767:Mefloquine
cancer du col de l’utérus; cervical cancer; mTOR signaling; mefloquine; mitochondrial respiration; méfloquine; respiration mitochondriale; signalisation de mTOR