Research ArticleCellular and Molecular
Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway
Daniel R. Premkumar, Esther P. Jane, Kimberly A. Foster and Ian F. Pollack
Journal of Pharmacology and Experimental Therapeutics August 2013, 346 (2) 201-210; DOI: https://doi.org/10.1124/jpet.113.204743
Daniel R. Premkumar
Department of Neurosurgery (D.R.P., E.P.J., K.A.F., I.F.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (D.R.P., E.P.J., I.F.P.), and University of Pittsburgh Cancer Institute Brain Tumor Program (I.F.P.), Pittsburgh, Pennsylvania
Esther P. Jane
Kimberly A. Foster
Ian F. Pollack
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.
Received March 12, 2013.
This work was supported by National Institutes of Health [Grant P01NS40923] (to I.F.P.); by the Walter L. Copeland fund of the Pittsburgh Foundation (to D.R.P. and K.A.F.); and by a grant from Ian's Friends Foundation (to I.F.P.) in honor of Ian Yagoda.
dx.doi.org/10.1124/jpet.113.204743.
You are going to email the following Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway
YM-155 Sensitizes Glioma Cells to TRAIL
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 201-210; DOI: https://doi.org/10.1124/jpet.113.204743
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