title: β-elemene reverses the drug resistance of lung cancer A549/DDP cells via the mitochondrial apoptosis pathway.
abstract: β-elemene (β-ELE) is a new anticancer drug extracted from Curcuma zedoaria Roscoe and has been widely used to treat malignant tumors. Recent studies have demonstrated that β-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of action of β-ELE, we investigated its effects on cisplatin-resistant human lung adenocarcinoma A549/DDP cells. The effects of β-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining and flow cytometry with Annexin V-FITC/PI double staining. Mitochondrial membrane potential was assessed using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorofluorescein-diacetate staining and flow cytometry. Cytosolic glutathione content was determined using GSH kits. The expression of cytochrome c, caspase-3, procaspase-3 and the Bcl-2 family proteins was assessed by western blotting. The results demonstrated that β-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, β-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, β-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and decreased the cytoplasmic glutathione levels in a time- and dose-dependent manner. The combination of β-ELE and cisplatin enhanced the protein expression of cytochrome c, caspase-3 and Bad, and reduced protein levels of Bcl-2 and procaspase-3 in the A549/DDP lung cancer cells. These results define a pathway of procaspase‑3-β-ELE function that involves decreased mitochondrial membrane potential, leading to apoptosis triggered by the release of cytochrome c into the cytoplasm and the modulation of apoptosis-related genes. The reversal of drug resistance of the A549/DDP cell line by β-ELE may be derived from its effect in inducing apoptosis.
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 355000, P.R. China.
authors.forename: Cheng-Cai
authors.initials: CC
authors.lastname: Yao
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 355000, P.R. China.
authors.forename: Yuan-Rong
authors.initials: YR
authors.lastname: Tu
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361001, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: College of Molecular Biology and Material of Xiamen University, Xiamen 361000, P.R. China.
authors.forename: Sheng-Fang
authors.initials: SF
authors.lastname: Ye
authors.affiliation: Department of Thoracic Surgery, Xiamen Traditional Chinese Medicine (TCM) Hospital Affiliated to Fujian University of TCM, Xiamen 361009, P.R. China.
authors.forename: Hao-Xin
authors.initials: HX
authors.lastname: Du
authors.affiliation: Department of Thoracic Surgery, Xiamen Traditional Chinese Medicine (TCM) Hospital Affiliated to Fujian University of TCM, Xiamen 361009, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D051025:bcl-Associated Death Protein; C445979:beta-elemene; D016572:Cyclosporine; D045304:Cytochromes c; D053148:Caspase 3; D005978:Glutathione; D002945:Cisplatin