Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

Abstract

Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several antiapoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.

Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis

“…The combination regimen also induced the expression of BAX, an apoptosis-related protein, in THP-1 cells. Moreover, it is known that treatment with HDAC inhibitors promotes BAX-dependent apoptosis in several cell types (24,25). In the present study, we showed that BAX also plays critical roles in Ara-C and VPA-induced apoptosis in AML cells.…”

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

“…Moreover, we (and others) have demonstrated that HDACi action is indeed tumor selective, impacting on proapoptotic pathways in cancer but not in normal cells (12,44). Specifically, our and other groups have shown that HDACi-induced cancer-selective apoptosis involves TRAIL reexpression in AMLs (12,45).…”

Death Receptors 4 and 5 Activate Nox1 NADPH Oxidase through Riboflavin Kinase to Induce Reactive Oxygen Species-mediated Apoptotic Cell Death

“…Cell Lines and Reagents-Human cervical carcinoma HeLa cells were purchased from the ATCC (Manassas, VA) and grown in DMEM supplemented with 10% (v/v) FCS, 100 units/ml penicillin, and 100 g/ml streptomycin (Invitrogen) as described previously (18,19). RFK-deficient HeLa shRFK cells that stably express RFK-specific shRNA (14) were a kind gift from Prof. Martin Krönke (University of Cologne) and were grown in the same conditions with wild type HeLa cells.…”