On the TRAIL of a new therapy for leukemia

Abstract

The cytokine TRAIL (tumor necrosis factor a-related apoptosisinducing ligand) as well as agonistic antibodies that bind to the TRAIL receptors, death receptor 4 (DR4) and DR5, are undergoing preclinical and early clinical evaluation as potential therapeutic agents for a variety of hematological and nonhematological malignancies. Here, we briefly review the normal biological function of TRAIL, the mechanism of cytotoxicity of TRAIL receptor ligands, and their effects on normal myeloid progenitors, myelodysplastic marrow and leukemic cells, including acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), in vitro. Recent observations suggesting that DR4 is the predominant receptor for the cytotoxic effects of TRAIL in CLL and that histone deacetylase inhibitors synergize with TRAIL in CLL in vitro are described and discussed. Collectively, the reviewed studies not only illustrate the potential therapeutic usefulness of TRAIL and the agonistic antibodies, but also highlight the need for additional preclinical evaluation of these agents.

Analysis of apoptosis regulatory genes altered by histone deacetylase inhibitors in chronic lymphocytic leukemia cells

“…Similar results have been described for the combination of TRAIL and the other HDACi Romidepsin and Valproate. 9,10 Thus, HDACi can activate both the death receptor and mitochondrial pathway concomitantly with transcriptional upregulation of specific pro-apoptotic and/or downregulation of …”

“…20,21 These synergistic apoptotic effects observed when HDACi are combined with TRAIL have also been described in CLL cells. 9,10 However, as different HDACi induce apoptosis in CLL cells as single agents, [11][12][13][14][15][16][17][18][19] it remains unclear whether signaling through death receptors is strictly necessary.…”

“…In this regard, different HDACi have been tested in primary cells from CLL patients showing pro-apoptotic activity. [9][10][11][12][13][14][15][16][17][18][19] One of the mechanisms of action of HDACi is to sensitize cancer cells to the induction of apoptosis through the death receptor pathway. 20,21 These synergistic apoptotic effects observed when HDACi are combined with TRAIL have also been described in CLL cells.…”

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

“…118 TRAIL is one of the members of the tumor necrosis factor superfamily known to induce apoptosis in a wide variety of cancer, but not normal, cells. 150,151 The use of TRAIL or of agonistic antibodies to TRAIL receptors as therapeutic agents for AML has been proposed. 151 A main problem, emerging from recent in vitro studies, is that AML blasts express low levels of TRAIL receptors and are therefore intrinsically resistant to this molecule.…”

“…150,151 The use of TRAIL or of agonistic antibodies to TRAIL receptors as therapeutic agents for AML has been proposed. 151 A main problem, emerging from recent in vitro studies, is that AML blasts express low levels of TRAIL receptors and are therefore intrinsically resistant to this molecule. 152,153 However, expression of TRAIL receptors could be increased by cotreating AML cells with a histone deacetylase inhibitor.…”