title: Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress.
abstract: Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines. The combination of artesunate and cisplatin is synergistic in targeting NPC cells in in vitro cellular culture system and in vivo xenograft tumor models. Artesunate inhibits phosphorylation of essential molecules involved in Akt/mTOR pathway in NPC cells, such as Akt, mTOR, and 4EBP1, and its inhibitory effects are partially abolished by overexpression of constitutively active Akt. In addition, artesunate also induces mitochondrial dysfunction and oxidative stress via inhibiting mitochondrial respiration, increasing levels of mitochondrial superoxide and cellular reactive oxygen species (ROS), leading to decreased ATP levels. Two ROS scavengers partially abolish the inhibitory effects of artesunate in NPC cells. These data suggest that both inhibition of Akt/mTOR pathway and induction of ROS are required for the action of artesunate in NPC cells. Our work demonstrates that artesunate is a potential candidate for NPC treatment. Our work also highlights the critical roles of Akt/mTOR pathway and mitochondrial function in NPC cells.
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ni
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Minghe
authors.initials: M
authors.lastname: Liu
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Lazhi
authors.initials: L
authors.lastname: She
authors.affiliation: Otolaryngology-Head and Neck Surgery, The Second Clinical Medical College, Yangtze University, Renmin Road 1, Jing Zhou, 434020, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D037621:Artemisinins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D000077332:Artesunate; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin
keywords: Akt/mTOR; artesunate; mitochondria; nasopharyngeal carcinoma; oxidative damage