title: 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.
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Zare-Abdollahi
authors.initials: ZA
authors.lastname: Davood
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Safari
authors.initials: S
authors.lastname: Shamsi
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Ghaedi
authors.affiliation: Department of Social Determinants of Health, National Institute of Health Research, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Riazi-Isfahani
authors.initials: RI
authors.lastname: Sahand
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Ghadyani
authors.initials: G
authors.lastname: Mojtaba
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Tabarraee
authors.initials: T
authors.lastname: Mahdi
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mirfakhraie
authors.initials: M
authors.lastname: Reza
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Javad
authors.initials: MJ
authors.lastname: Ebrahimi
authors.affiliation: Department of Cellular and Molecular Biology, Islamic Azad University East Tehran, Tehran, Iran.
authors.forename: Reyhaneh Sadat
authors.initials: RS
authors.lastname: Miri-Moosavi
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Sara
authors.initials: S
authors.lastname: Boosaliki
authors.affiliation: Faculty of Medicine, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. davood_omrani@sbmu.ac.ir.
authors.forename: Omrani Mir
authors.initials: OM
authors.lastname: Davood
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D014635:Valproic Acid; D002738:Chloroquine
keywords: AML; ATG7; Acute myeloid leukemia; Apoptosis; Autophagy; BECN1; Cytogenetics; HDAC; MST1; MST2; RASSF1A; VPA, chloroquine; Valproic acid