Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

Abstract

Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

“…Recently it has been identified that VPA is an effective inhibitor of HDAC activity at physiologically relevant concentrations. It is also becoming evident that the efficacy of VPA in vivo is in part due to inhibition of cancer cell migration, invasion and angiogenesis (Chou et al, 2011;Wedel et al, 2011;Leiva et al, 2012). This gave us the inspiration to see whether VPA could have the similar effects in ovarian cancer.…”

A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance

“…24 Short-term in vivo treatment of preleukemic mice with the class I HDACi VPA phenocopied the effect of Hdac1 knock-down during PML-RAR-mediated leukemogenesis with expansion of the Gr1 1 /cKit 1 population and accelerated disease. Intriguingly, this phenomenon was not observed after treatment of premalignant Em-myc mice with VPA, indicating that a tumor-type or oncogene-specific effect may be at play (data not shown).…”

“…For APL mice treatment, 2*10^5 APL cells were injected intravenously into nonirradiated congenic-recipient mice (C57Bl/6-Ly5.1) and then treated with VPA (intraperitoneally at the dose of 400 mg/kg twice a day for 4 weeks) when the blast cells (Ly5.2) in peripheral blood reached 5% to 10%. 24 Quantitative polymerase chain reaction Total RNA was purified using RNeasy Mini Kit (QIAGEN, Valencia, CA), quantified and reverse transcribed. From 5 to 10 ng of cDNA were used to perform quantitative polymerase chain reaction using SYBR Green Reaction Mix (Perkin Elmer, Boston, MA).…”

Epigenetic alterations in acute myeloid leukemias

“…Complementing these studies, the HDAC inhibitor valproic acid (mainly acting on class I HDACs) was shown to behave differently at the preleukemic and leukemic stages, mimicking the HDAC1 knockdown phenotype [112]. Moreover, in established leukemia, valproic acid showed different effects on the bulk of tumor cells and LICs, being mostly effective on the bulk of APL blasts and having only a mild effect on LICs [115]. From these studies, it therefore appears that HDACs not only have different roles at different stages of tumorigenesis, but also have different biological effects in different tumor cell subtypes (LICs versus the bulk of tumor cells).…”