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

• Published in: Medical oncology (Northwood, London, England) London, England), 2013-03, Vol.30 (1), p.488-488, Article 488
• Main Authors: Li, Q. Quentin, Wang, Gangduo, Huang, Furong, Li, Jueli M., Cuff, Christopher F., Reed, Eddie
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; CDC2 Protein Kinase; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Checkpoint Kinase 2; Cisplatin - pharmacology; Cyclin B - metabolism; Cyclin-Dependent Kinases; G2 Phase Cell Cycle Checkpoints - drug effects; Hematology; Humans; Internal Medicine; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Oncology; Original Paper; Pathology; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - metabolism; Sesquiterpenes - pharmacology
• ISSN: 1357-0560; 1559-131X
• DOI: 10.1007/s12032-013-0488-9

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.