beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis.
beta-Elemene, a new plant-derived anticancer agent with low toxicity, has been reported to be effective in the treatment of leukemia and solid tumors. In the current study, we explored the therapeutic application of beta-elemene in sensitizing lung cancer cells to cisplatin. beta-Elemene considerably enhanced the inhibitory effect of cisplatin on cell proliferation in a time- and dose-dependent manner in the human non-small cell lung cancer (NSCLC) cell lines H460 and A549. Furthermore, this effect of beta-elemene on cisplatin activity occurred through the induction of apoptosis in NSCLC cells, as assessed by an ELISA-based assay, TUNEL assay and annexin V binding assay. Consistent with these results, the protein levels of Bax and phospho-Bcl-2 increased and those of Bcl-2 and XIAP decreased in cells treated with beta-elemene in combination with cisplatin, compared with the levels in cells treated with either agent alone. Finally, beta-elemene augmented the cisplatin-induced increases in caspase-3, -7, -9 and -10 activities and cleaved caspase-3, -9 and poly(ADP-ribose) polymerase levels in NSCLC cells. These observations suggest that beta-elemene sensitizes NSCLC cells to cisplatin via a mitochondria-mediated intrinsic apoptosis pathway involving Bcl-2 family proteins and IAPs (inhibitor of apoptosis proteins). Our data provide a rationale for developing a combination of beta-elemene and cisplatin as a regimen for the treatment of lung carcinoma and other cisplatin-resistant tumors.
Li
Qingdi Q
QQ
The Mary Babb Randolph Cancer Center and Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University of Medicine, Morgantown, WV 26506, USA. liquenti@mail.nih.gov
Wang
Gangduo
G
Zhang
Manchao
M
Cuff
Christopher F
CF
Huang
Lan
L
Reed
Eddie
E
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; C445979:beta-elemene; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002945:Cisplatin