Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo

Abstract

NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.

The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy

“…6 These agents are capable of mediating a variety of antitumor effects, such as induction of apoptosis, 7,11 cell-cycle arrest, 12,13 and inhibition of angiogenesis. 14,15 Although LBH589 and LAQ824 have proven therapeutic effects in preclinical models 7,8,12,14,15 and in human patients, 3,5,6 it is not clear which of their biologic action(s) account(s) for their antitumor efficacy in vivo.…”

“…14,15 Both LAQ824 and LBH589 are particularly effective in killing primary leukemia and lymphoma cells and established tumorderived cell lines in vitro, [7][8][9][10][11]13 and studies using xenotransplantation tumor models have demonstrated therapeutic efficacy in vivo. 7,8,12,14,15 Determining whether HDACi-mediated tumor cell apoptosis is important for the therapeutic activity of the drugs remains an important unanswered question. Moreover, although LAQ824 and LBH589 have been shown to induce morphologic and biochemical changes associated with apoptosis, exactly how these drugs trigger the apoptotic pathway remains to be elucidated.…”

“…3 LAQ824 and LBH589 are members of the hydroxamic acid class of HDACi that show broad enzyme inhibitory activity in the low nanomolar range 4 and have progressed through preclinical development into early-phase clinical trials. 5,6 These HDACi can have diverse anticancer activities, including induction of tumor cell apoptosis, [7][8][9][10][11] inhibition of cell-cycle progression, 12,13 and suppression of angiogenesis. 14,15 Both LAQ824 and LBH589 are particularly effective in killing primary leukemia and lymphoma cells and established tumorderived cell lines in vitro, [7][8][9][10][11]13 and studies using xenotransplantation tumor models have demonstrated therapeutic efficacy in vivo.…”

“…5,6 These HDACi can have diverse anticancer activities, including induction of tumor cell apoptosis, [7][8][9][10][11] inhibition of cell-cycle progression, 12,13 and suppression of angiogenesis. 14,15 Both LAQ824 and LBH589 are particularly effective in killing primary leukemia and lymphoma cells and established tumorderived cell lines in vitro, [7][8][9][10][11]13 and studies using xenotransplantation tumor models have demonstrated therapeutic efficacy in vivo. 7,8,12,14,15 Determining whether HDACi-mediated tumor cell apoptosis is important for the therapeutic activity of the drugs remains an important unanswered question.…”

The novel histone deacetylase inhibitor NVP-LAQ824: an addition to the therapeutic armamentarium in leukemia?

“…For example, in the case of Bcr/Abl þ leukemic cells, HDACIs including NVP-LAQ824 and SAHA have now been reported to potentiate the antileukemic activity of imatinib mesylate. 1,16,25,26 Moreover, HDACIs, including NVP-LAQ824, have been shown to interact synergistically in human leukemia cells with additional novel agents, including TRAIL 27,28 and the cyclin-dependent kinase inhibitor flavopiridol. 29 Whether such preclinical findings will translate directly into improved therapeutic outcomes in patients with leukemia or other hematologic malignancies remains to be determined.…”