title: Promotion of p53 expression and reactive oxidative stress production is involved in zerumbone-induced cisplatin sensitization of non-small cell lung cancer cells.
abstract: p53 signaling plays an important role in cell death. Zerumbone, a natural cyclic sesquiterpene, has shown cytotoxic activity against many cancers. This study was done to investigate the anticancer effects of zerumbone on non-small cell lung cancer (NSCLC) cells and explored the involvement of p53 signaling. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium assay. Apoptosis was confirmed by annexin-V/propidium iodide staining and caspase activity assay. Mitochondrial membrane potential (Δφm) and reactive oxygen species (ROS) production were measured by flow cytometry. Depletion of p53 was achieved by transfection of specific small interfering RNA. Gene expression changes were determined by Western blot analysis. Zerumbone treatment caused a dose-dependent inhibition of A549 and H460 NSCLC cell viability. Zerumbone-induced mitochondrial apoptosis of NSCLC cells, evidenced loss of Δφm, release of mitochondrial cytochrome c, and activation of caspase-9 and -3. There was increased p53 and Bax expression and ROS production in zerumbone-treated cells. Downregulation of p53 or scavenging ROS interfered with the pro-apoptotic action of zerumbone. Combinational treatment with zerumbone and cisplatin significantly accelerated apoptosis and promoted p53 expression and ROS production in NSCLC cells, compared with each alone. These findings demonstrate that zerumbone induces mitochondrial apoptosis and enhances the susceptibility to cisplatin in NSCLC cells, which are, at least partially, mediated through activation of p53 signaling and promotion of ROS generation. This study may provide a rationale for the potential clinical application of zerumbone as a chemotherapeutic agent against NSCLC.
authors.affiliation: Department of Respiratory Medicine, Wuhan General Hospital of Guangzhou Command, Wuhan, China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Respiratory Medicine, Wuhan General Hospital of Guangzhou Command, Wuhan, China.
authors.forename: Qunli
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Respiratory Medicine, Wuhan General Hospital of Guangzhou Command, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Wuhan General Hospital of Guangzhou Command, Wuhan, China.
authors.forename: Haichao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China. Electronic address: whouwei@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C403304:zerumbone; D002945:Cisplatin
keywords: Apoptosis; Chemosensitivity; Combination therapy; Natural products; p53