1906

While tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising new agent for the treatment of cancer,resistance to TRAIL remains a therapeutic challenge. Identification of agents that can be used in combination with TRAIL to enhance apoptosis in leukemia cells would increase the potential utility of this agent as a leukemia therapeutic. Here we show that 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor γ (PPARγ), can sensitize TRAIL-resistant HL-60 cells to apoptosis induction by TRAIL. The sensitization to TRAIL-induced apoptosis by 15d-PGJ2 was not blocked by PPARγ inhibitor (GW9662), suggesting a PPARγ-independent mechanism. This process was accompanied by activation of caspase 8, caspase 9, and caspase-3 and was concomitant with Bid and PARP cleavage. We observed the significant decrease of XIAP, Bcl-2, and c-FLIP by cotreatment with 15d-PGJ2 and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ2 and TRAIL. Furthermore, Akt inactivation by Akt inhibitor IV or transfection of dominant negative (DN)-Akt expression vector sensitizes HL-60 cells to TRAIL, indicating a key role for Akt inhibition in these events. Taken together, these findings indicate that15d-PGJ2 may have a promising activity in augmenting TRAIL-induced apoptosis of human leukemia HL-60 cells through inhibition of Akt.

This study was supported by the Korea Science and Engineering Foundation through the Medical Research Center for Cancer Molecular Therapy at Dong-A University.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA