Induction of apoptosis by the death
ligand tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is a promising antitumor
therapy. However, not all
tumor cells are sensitive to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Inhibitor of apoptosis family member
survivin is constitutively activated in various
cancers and blocks apoptotic signaling. Recently, we demonstrated that
YM-155 [3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(pyrazin-2-ylmethyl)-4,9-dihydro-3H-naphtho[2,3-d]imidazol-1-ium
bromide], a small molecule inhibitor, downregulates not only
survivin in
gliomas but also
myeloid cell leukemia sequence 1 (Mcl-1), and it upregulates proapoptotic Noxa levels. Because Mcl-1 and
survivin are critical mediators of resistance to various anticancer
therapies, we questioned whether
YM-155 could sensitize resistant
glioma cells to TRAIL. To address this hypothesis, we combined
YM-155 with TRAIL and examined the effects on cell survival and apoptotic signaling. TRAIL or
YM-155 individually induced minimal killing in highly resistant U373 and LNZ308 cell lines, but combining TRAIL with
YM-155 triggered a synergistic proapoptotic response, mediated through
mitochondrial dysfunction via activation of caspases-8, -9, -7, -3,
poly-ADP-ribose polymerase, and Bid. Apoptosis induced by combination treatments was blocked by
caspase-8 and pan-
caspase inhibitors. In addition, knockdown of Mcl-1 by RNA interference overcame apoptotic resistance to TRAIL. Conversely, silencing Noxa by RNA interference reduced the combined effects of
YM-155 and TRAIL on apoptosis. Mechanistically, these findings indicate that
YM-155 plays a role in counteracting
glioma cell resistance to TRAIL-induced apoptosis by downregulating Mcl-1 and
survivin and amplifying mitochondrial signaling through intrinsic and extrinsic apoptotic pathways. The significantly enhanced antitumor activity of the combination of
YM-155 and TRAIL may have applications for
therapy of
malignant glioma.