title: Sensitization of lung cancer cells to cisplatin by β-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of β-elemene and its synthetic analogs.
abstract: The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that β-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether β-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. β-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, β-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G(2)/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, β-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21(Cip1/Waf1), p27(Kip1), and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the β-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G(2)/M. A comparison of the cytotoxic efficacies of β-elemene and three synthetic analogs (β-elemenol, β-elemenal, and β-elemene fluoride) in the two lung cancer cell lines revealed that β-elemenol and β-elemene fluoride had the same antitumor efficacy as β-elemene, whereas β-elemenal was appreciably more potent than β-elemene. Thus, although all three synthetic analogs of β-elemene considerably suppressed NSCLC cell growth and proliferation, β-elemenal may have greater potential as an anticancer alternative to β-elemene in treating lung cancer and other tumors.
authors: West Virginia University School of Medicine, Morgantown, WV 26506, USA. liquenti@mail.nih.gov
authors: Q Quentin
authors: QQ
authors: Li
authors: Gangduo
authors: G
authors: Wang
authors: Furong
authors: F
authors: Huang
authors: Jueli M
authors: JM
authors: Li
authors: Christopher F
authors: CF
authors: Cuff
authors: Eddie
authors: E
authors: Reed
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2; D002945:Cisplatin / Q000494:pharmacology*; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019926:Cyclin B; D012717:Sesquiterpenes; C445979:beta-elemene; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin
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