Because Bcl-2 family members inhibit the ability of
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) to induce apoptosis, we investigated whether
ABT-737, a small molecule Bcl-2 inhibitor, enhances TRAIL killing. We demonstrate that a combination of
ABT-737 and TRAIL induced significant cell death in multiple
cancer types, including renal, prostate, and
lung cancers, although each agent individually had little activity in these
tumor cells. All of these cell lines expressed the Mcl-1
protein that is known to block the activity of
ABT-737 and TRAIL but did not block the synergy between these agents. However, Bax-deficient cell lines, including DU145 and HCT116 cells and those cell lines expressing low levels of TRAIL receptor, were resistant to apoptosis induced by these agents. To understand how
ABT-737 functions to markedly increase TRAIL sensitivity, the levels of specific death-inducing signaling complex components were evaluated. Treatment with
ABT-737 did not change the levels of c-FLIP, FADD, and
caspase-8 but up-regulated the levels of the TRAIL
receptor DR5. DR5 up-regulation induced by
ABT-737 treatment occurred through a transcriptional mechanism, and mutagenesis studies demonstrated that the
NF-kappaB site found in the DR5 promoter was essential for the ability of
ABT-737 to increase the levels of this
mRNA. Using
luciferase reporter plasmids,
ABT-737 was shown to stimulate
NF-kappaB activity. Together, these results demonstrate that the ability of
ABT-737 and TRAIL to induce apoptosis is mediated through activation of both the extrinsic and intrinsic pathways. Combinations of
ABT-737 and TRAIL can be exploited therapeutically where antiapoptotic Bcl-2 family members drive
tumor cell resistance to current anticancer
therapies.