title: Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway.
abstract: Deregulation of PI3K/Akt/mTOR pathway has been recently identified to play a crucial role in the progress of human gastric cancer. In this study, we show that mefloquine, a FDA-approved anti-malarial drug, effectively targets human gastric cancer cells. Mefloquine potently inhibits proliferation and induces apoptosis of a panel of human gastric cancer cell lines, with EC50 ∼ 0.5-0.7 μM. In two independent gastric cancer xenograft mouse models, mefloquine significantly inhibits growth of both tumors. The combination of mefloquine with paclitaxel enhances the activity of either drug alone in in vitro and in vivo. In addition, mefloquine potently decreased phosphorylation of PI3K, Akt, mTOR and rS6. Overexpression of constitutively active Akt significantly restored mefloquine-mediated inhibition of mTOR phosphorylation and growth, and induction of apoptosis, suggesting that mefloquine acts on gastric cancer cells via suppressing PI3K/Akt/mTOR pathway. We further show that mefloquine-mediated inhibition of Akt/mTOR singaling is phosphatase-dependent as pretreatment with calyculin A does-dependently reversed mefloquine-mediated inhibition of Akt/mTOR phosphorylation. Since mefloquine is already available for clinic use, these results suggest that it is a useful addition to the treatment armamentarium for gastric cancer.
authors.affiliation: Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, PR China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Academic Affairs, Hubei University of Medicine, Shiyan, Hubei Province, PR China.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of Oncology, Xiangyang Central Hospital, Shiyan, Hubei Province, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, PR China. Electronic address: maoojun_di@163.com.
authors.forename: Maojun
authors.initials: M
authors.lastname: Di
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015767:Mefloquine / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015767:Mefloquine; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Gastric cancer; Mefloquine; PI3K/Akt/mTOR signaling; Paclitaxel; Synergy