Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents

Abstract

Several new therapeutic strategies are now considered for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). These enzymes alter the acetylation of several proteins, including histones and transcription factors, as well as several other proteins directly involved in the regulation of cell proliferation, differentiation and apoptosis. Valproic acid (VPA) is a HDAC inhibitor that has been investigated in several clinical AML studies, usually in combination with all-trans retinoic acid (ATRA) for treatment of patients unfit for intensive chemotherapy, for example older patients, and many of these patients have relapsed or primary resistant leukemia. The toxicity of VPA in these patients is low and complete hematological remission lasting for several months has been reported for a few patients (<5% of included patients), but increased peripheral blood platelet counts are seen for 30 to 40% of patients and may last for up to 1 to 2 years. We review the biological effects of VPA on human AML cells, the results from clinical studies of VPA in the treatment of AML and the evidence for combining VPA with new targeted therapy. However, it should be emphasized that VPA has not been investigated in randomized clinical studies. Despite this lack of randomized studies, we conclude that disease-stabilizing treatment including VPA should be considered especially in unfit patients, because the possibility of improving normal blood values has been documented in several studies and the risk of clinically relevant toxicity is minimal.

NFκB- and AP-1-mediated DNA looping regulates matrix metalloproteinase-9 transcription in TNF-α-treated human leukemia U937 cells

“…Obviously, elimination of TNF--mediated MMP-9 expression would be beneficial for suppressing the progression of leukemia. Some studies suggested that the HAT inhibitor could be useful for leukemia therapy [50,51]. Nevertheless, the use of HDAC inhibitors should be carefully evaluated because the data presented in this study show that TSA induces MMP-9 up-regulation in leukemia cells.…”

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy

“…Several approaches to improving retinoid efficacy have been examined in experimental studies. These include combining ATRA with inhibitors of growth factor signaling pathways [45] as well as proteasome pathway inhibitors [46] and histone deacetylase inhibitors [47,48]. At least one novel retinoid (Tamibarotene) has been tested [49] and is currently under investigation in PML [50].…”

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

“…However, an alternative strategy could be to combine CDC25 inhibitors with low-toxicity disease-stabilizing strategies in patients that are unfit for the intensive and potentially curative treatment. If this last strategy is considered, CDC25 inhibitors may be combined with all-trans-retinoic acid (ATRA) plus valproic acid [167], low-dose cytarabine [168], hydroxyurea and/or 6-mercaptopurine [167][168][169][170][171].…”