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

TNF-related apoptosis-inducing ligand (TRAIL/Apo- 2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmem-brane receptors (TRAIL-R1/DR4 and TRAIL-R2/ DR5). TRAIL known to activate NF-κB in number of tumor cells including A549 (wt p53) and NCI- H1299 (null p53) lung cancer cels exerts relati-tumor cel lines without much effect on the normal cels. We set out to identify an agent that would sensitize lung cancer cels to TRAIL-induced apo-ptosis through inhibition of NF-κB activation. We found that triptolide, an oxygenated diterpene ex-tracted and purified from the Chinese herb Tri-pterygium wilfordi sensitized A549 and NCI-H1299 cels to TRAIL-induced apoptosis through inhibi-tion 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 cels to TRAIL-induced apoptosis. Tripto-lide did not block DNA binding of NF-κB activated by TRAIL as in the case of TNF-α. It has ben already proven that triptolide blocks transactiva-tion of p65 which plays a key role in NF-κB acti-vation. These observations suggest that triptolide may be a potentialy useful drug to enhance KCI Citation Count: 88