Valproic acid may exerts its cytotoxic effect through rassf1a expression induction in acute myeloid leukemia

Abstract

In acute myeloid leukemia (AML), despite the acceptance of standard intensive chemotherapy as an optimal induction regimen for all age groups, in the elderly patients, the best treatment should meet the challenge of multiple factors like age, comorbidities, and cytogenetics, making them ineligible for standard induction chemotherapy. Using the current low-intensity therapies like decitabine, azacitidine, and low-dose cytarabine as a single arm, outcomes for these patients remain poor. As a histone deacetylase inhibitor valproic acid (VPA) exhibit anticancer activity by triggering apoptosis, the mechanism of which is not yet completely clarified. To explore the possible connection between VPA treatment and the Hippo pathway as an apoptosis stimulating route, we also explore the expression of major components of this pathway and for the first time we postulate a relationship between VPA treatment and cell death induction through RASSF1A expression induction. Furthermore, we demonstrate that autophagy inhibition by chloroquine (CQ) significantly augmented the cytotoxic effect of VPA on AML cells, especially in those with unfavorable and normal karyotype. Regarding that VPA and CQ are well-tolerated drugs and our presumptive results of usefulness of VPA + CQ in three cytogenetic risk groups of AML, this combinatorial therapy could represent an attractive treatment option for older AML patients unfit for intensive therapy.

Role of HDACs in normal and malignant hematopoiesis

“…To date, the different mechanisms of HDACis combined with chemotherapeutic agents such as topoisomerase inhibitors, platinumbased chemotherapeutics, proteasome inhibitors, tyrosine kinase pathway inhibitors and epigenetic modifiers for advanced or drug-resistant hematological malignancies include (1) acetylating histones and inducing p21-CDK-mediated cell cycle arrest; (2) inducing apoptosis by regulating the expression of pro-and antiapoptotic genes through the intrinsic or extrinsic pathway; (3) inducing DNA damage and oxidative stress; (4) activating BTK (in CLL) or inhibiting ERK (in MM) and AKT (in CML) signaling pathways; and (5) regulating the expression of drug resistance-related molecules, such as downregulating BCR-ABL and upregulating Bim in hematological malignancies and downregulating CD44 in multiple myeloma (MM), NF-κB in ALL, γ-catenin in CML, and BRCA1, CHK1 and RAD51 in AML [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Specific combination strategies and their corresponding mechanisms are summarized in Table 3 [146][147][148][149][150][151][152][153][154][155]. Moreover, two-phase I clinical trials were carried out to assess the DNA methyltransferase (5-azacitidine) and HDACi (phenylbutyrate) for the treatment of hematological malignancies.…”

miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells

“…The significance of the Hippo-YAP1 signaling pathway has recently been identified in myeloma cells [21–23]. However, the contribution of Hippo signaling to the pathophysiology of AML remains unclear although a few reports mentioned Hippo signaling in AML cells [21, 24]. Regarding MSCs in patients with AML, it has been demonstrated that deregulation of proteoglycans, adhesion molecules, expression of cytokines, metabolic and endocytosis pathways could be detected by whole-exome sequencing [25].…”

Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

“…However, additional mechanisms may contribute to the antiproliferative and proapoptotic effects of valproic acid. First, the hippo signaling pathway is important for regulation of proliferation and apoptosis, and altered signaling through this pathway (possibly due to the induction of RASSF1A expression) may be an antileukemic mechanism especially in patients with normal and adverse karyotype [ 23 ]. Second, valproic acid in combination with interferon (IFN)-α alters the activation/phosphorylation of Akt, ERK1/2, p38, and p53 [ 24 ].…”