The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most norma l cells. Recent studies have revealed an unforeseen toxicity of TRAIL towar d normal human hepatocytes, thereby bringing into question the safety of sy stemic administration of TRAIL in humans with cancer. We found that SW480 c olon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which a re sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD -FMK from TRAIL-induced apoptosis, However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to T RAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 a nd SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD- FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposur e. We confirmed that normal human Liver cells are sensitive to TRAIL. Moreo ver, we found that normal human Liver cells could be protected from TRAIL-i nduced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief ex posure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HC T116 cells. Because some cancer cell lines are not protected from TRAIL-med iated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 in hibition during TRAIL administration may widen the therapeutic window and a llow cancer cell killing white protecting normal liver cells, This strategy could be further developed in the effort to advance TRAIL into clinical tr ials.