Sesquiterpene Lactone Parthenolide Markedly Enhances Sensitivity of Human A549 Cells to Low-Dose Oxaliplatin via Inhibition of NF-κB Activation and Induction of Apoptosis

Abstract

Aberrant activation of NF-κB 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-κB activation may be a useful strategy in cancer therapy. Thus, this study was performed to explore the effect of parthenolide, a natural NF-κB 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. PGE₂ production in culture supernatants was detected by competitive ELISA, while expression of NF-κB/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-κB/p65, COX-2, and PGE₂ 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-κB 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.

Key words

parthenolide - oxaliplatin - A549 cells - NF‐κB - apoptosis

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1 These authors contributed to this work equally.