Lung cancer is the leading cause of cancer death among the men and women in the United States. Therefore, there is a need to develop compounds that can effectively treat this disease. Elemene, an extract from the ginger plant, is a new antitumor drug, which was approved for the treatment of cervical cancer and carcinoma of the lung, liver, and brain in China, and is now in application for clinical studies in the United States. However, the mechanism underlying the effect of Elemene in lung cancer remains unknown. This study investigated the ability of Elemene to induce cell cycle arrest, to trigger apoptosis, and to sensitize cancer cells to cisplatin in non-small cell lung cancer (NSCLC) cells. We showed that Elemene has an effect on cell-killing in the human NSCLC cell lines H460 and A549, as determined by the MTT assay. Elemene was also found to increase cisplatin cytotoxicity and enhance cisplatin sensitivity in these cells. Moreover, we demonstrated, by using FACS analysis, Cell Death Detection ELISA Kit, and the TUNEL assay, that Elemene or cisplatin independently induced cell cycle arrest and apoptosis in a time- and dose-dependent manner in these systems and that a synergistic effect in this regard was seen when cells were treated with both agents. Further study showed that Elemene decreased the phosphorylation of cdk1 and cdk2, but increased the activity of caspases, including caspase-9, caspase-3, caspase-7, caspase-8, and caspase-10. Finally, we demonstrated that Elemene reduced the expression of cyclin A and cyclin B1, but increased the level of p27 protein in NSCLC cells, indicating that Elemene modulates the activity of the regulatory proteins in cell cycle and apoptosis in these cells. These findings suggest that Elemene may trigger cell death and reverse drug resistance to cisplatin in human NSCLC via the regulation of cell cycle control and apoptotic signals. This study was supported by NIH/NCRR grant P20 RR16440.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]