Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-κB activation

Abstract

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmembrane receptors (TRAIL-R1/DR4 and TRAIL-R2/ DR5). TRAIL known to activate NF-κB in number of tumor cells including A549 (wt p53) and NCl-H1299 (null p53) lung cancer cells exerts relatively selective cytotoxic affects to the human tumor cell lines without much effect on the normal cells. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-κB activation. We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCl-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-κB activation. Pretreatment with MG132 which is a well-known NF-κB inhibitor by blocking degradation of IκBα also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-κB activated by TRAIL as in the case of TNF-α. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-κB activation. These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.