Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been re ported to induce apoptosis in various tumor cells but not in nontransformed , normal cells(1-3). Preclinical studies in mice and nonhuman primates have shown that administration of TRAIL can induce apoptosis in human tumors, b ut that no cytotoxicity to normal organs or tissues is found(3,4). The susc eptibility of tumor cells to TRAIL and an apparent lack of activity in norm al cells has lead to a proposal to use TRAIL in cancer therapy. Here, we as sessed the sensitivity of hepatocytes from rat, mouse, rhesus monkey and hu man livers to TRAIL-induced apoptosis. TRAIL induced apoptosis in normal hu man hepatocytes in culture but not in hepatocytes isolated from the other s pecies. Human hepatocytes showed characteristic features of apoptosis, incl uding cytoplasmic shrinkage, the activation of caspases and DNA fragmentati on. Apoptosis and cell death in human hepatocytes was massive and rapid, oc curring in more than 60% of the cells exposed to TRAIL within 10 hours. The se results indicate that there are species differences in sensitivity to TR AIL, and that substantial liver toxicity might result if TRAIL were used in human cancer therapy.