title: VCPA, a novel synthetic derivative of α-tocopheryl succinate, sensitizes human gastric cancer to doxorubicin-induced apoptosis via ROS-dependent mitochondrial dysfunction.
abstract: Gastric carcinoma is a common malignant disease worldwide and has a dismal prognosis. Doxorubicin (DOX), one of the most widely used chemotherapeutic agents, has limited use because of its side effects and the development of tumor-cell resistance. Combinations of doxorubicin and non-cross-resistant agents have been required for adjuvant chemotherapy of gastric cancer. Here, we report that VCPA, a novel synthetic derivative of α-Tocopheryl Succinate, induced apoptosis via production of reactive oxygen species (ROS). When used in combination with doxorubicin, lower doses of VCPA sensitized human gastric cancer cells to DOX-induced apoptosis. The DOX/VCPA combination treatment caused an imbalance in the ratio of Bcl-2 to Bax and induced a lethal mitochondrial dysfunction. MAPKs were also activated in response to the DOX/VCPA treatment but played a protective role in DOX-induced cell death. In vivo studies further confirmed the sensitizing effect of VCPA. Combining DOX with VCPA markedly inhibited tumor growth in a tumor xenograft model of human gastric cancer. Taken together, our study revealed that VCPA, through increased ROS production, could synergize with DOX and circumvent DOX resistance in human gastric cancer cells.
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Jiuyang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Leng
authors.affiliation: Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China; Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital, The Capital Medical University, Beijing, China. Electronic address: liyansd2@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D024502:alpha-Tocopherol
keywords: Human gastric cancer; Mitochondrial apoptotic pathway; ROS