Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is a potent inducer of apoptosis of transformed and
cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with
cancer. We found that SW480
colon adenocarcinoma, or H460
non-small cell lung cancer cell lines, which are 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 TRAIL, were protected by
Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and 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 exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to
Z-LEHD-FMK. A similar brief exposure to TRAIL plus
Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some
cancer cell lines are not protected from TRAIL-mediated killing by
Z-LEHD-FMK, we believe that a brief period of
caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow
cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials.