Sesquiterpene lactone parthenolide markedly enhances sensitivity of human A549 cells to low-dose oxaliplatin via inhibition of NF-kappaB activation and induction of apoptosis.
Aberrant activation of NF-kappaB has been proposed as the major cause of chemoresistance in lung cancer. Low-dose chemotherapeutic agents with limited toxicity and achieving profoundly enhanced efficacy by blocking NF-kappaB activation may be a useful strategy in cancer therapy. Thus, this study was performed to explore the effect of parthenolide, a natural NF-kappaB inhibitor, on human lung cancer A549 cells treated with low-dose oxaliplatin, as well as to determine the potential mechanisms involved. We incubated A549 cells with different concentrations of parthenolide in the absence or presence of a low-dose of oxaliplatin for 48 h. Then, cell proliferation was determined by MTT assay, and flow cytometry was used to study apoptosis. PGE(2) production in culture supernatants was detected by competitive ELISA, while expression of NF-kappaB/p65, COX-2, caspase-3 and caspase-9 proteins were analyzed by Western blot. Finally, compared to parthenolide or oxaliplatin alone, significant improvements in cell apoptosis and growth inhibition indexes were observed in the combined treatment. NF-kappaB/p65, COX-2, and PGE(2) expression were suppressed by the co-application; meanwhile, caspase-3 and caspase-9 proteins were obviously activated. These findings indicate that parthenolide could markedly enhance sensitivity of A549 cells to low-dose oxaliplatin by inhibiting NF-kappaB activation and inducing apoptosis. Parthenolide in combination with a low dose of oxaliplatin may be a beneficial chemotherapeutic strategy for patients who cannot tolerate the severe side effects of the drug at therapeutic concentrations.
Fang
Liang-Jie
LJ
Department of Respiratory Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
Shao
Xue-Ting
XT
Wang
Shuo
S
Lu
Guo-Hua
GH
Xu
Tao
T
Zhou
Jian-Ying
JY
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D031203:Tanacetum / Q000737:chemistry
D000970:Antineoplastic Agents; D007783:Lactones; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D010936:Plant Extracts; D012717:Sesquiterpenes; D000077150:Oxaliplatin; C002669:parthenolide; D051546:Cyclooxygenase 2; D053148:Caspase 3; D053453:Caspase 9; D015232:Dinoprostone