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.
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We would like to thank the patients who participated in this study.
Compliance with ethical standard
All samples were included after obtaining Institutional Review Board Approval and informing consent in accordance with the Declaration of Helsinki.
Conflicts of interest
Gale RP, Wiernik PH, Lazarus HM. Should persons with acute myeloid leukemia have a transplant in first remission? Leukemia. 2014;28(10):1949–52.CrossRefPubMedGoogle Scholar
Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007;25(14):1908–15.CrossRefPubMedGoogle Scholar
Jackson GH, Taylor PR. Acute myeloid leukaemia: optimising treatment in elderly patients. Drugs Aging. 2002;19(8):571–81.CrossRefPubMedGoogle Scholar
Juliusson G et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179–87.CrossRefPubMedGoogle Scholar
Alibhai SM et al. Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer. 2009;115(13):2903–11.CrossRefPubMedGoogle Scholar
Luger SM. Treating the elderly patient with acute myelogenous leukemia. Hematology Am Soc Hematol Educ Prog. 2010;2010:62–9.Google Scholar
Bug G et al. Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia. Haematologica. 2007;92(4):542–5.CrossRefPubMedGoogle Scholar
Cheng YC et al. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res. 2007;31(10):1403–11.CrossRefPubMedGoogle Scholar
Cimino G et al. Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. Cancer Res. 2006;66(17):8903–11.CrossRefPubMedGoogle Scholar
Kuendgen A et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006;106(1):112–9.CrossRefPubMedGoogle Scholar
Kuendgen A et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84 Suppl 1:61–6.CrossRefPubMedGoogle Scholar
Grusche FA, Richardson HE, Harvey KF. Upstream regulation of the hippo size control pathway. Curr Biol. 2010;20(13):R574–82.CrossRefPubMedGoogle Scholar
Grimwade D et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354–65.CrossRefPubMedGoogle Scholar
Isakson P et al. Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. Blood. 2010;116(13):2324–31.CrossRefPubMedGoogle Scholar
Torgersen ML et al. Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells. Blood. 2013;122(14):2467–76.CrossRefPubMedGoogle Scholar
Thomas S et al. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat. 2011;130(2):437–47.CrossRefPubMedPubMedCentralGoogle Scholar
Zapotocky M et al. Valproic acid triggers differentiation and apoptosis in AML1/ETO-positive leukemic cells specifically. Cancer Lett. 2012;319(2):144–53.CrossRefPubMedGoogle Scholar
Petruccelli LA et al. Expression of leukemia-associated fusion proteins increases sensitivity to histone deacetylase inhibitor-induced DNA damage and apoptosis. Mol Cancer Ther. 2013;12(8):1591–604.CrossRefPubMedGoogle Scholar
Hodges-Gallagher L et al. Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat. 2007;105(3):297–309.CrossRefPubMedGoogle Scholar
Matallanas D et al. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell. 2007;27(6):962–75.CrossRefPubMedPubMedCentralGoogle Scholar
Issa JP et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015;121(4):556–61.CrossRefPubMedGoogle Scholar
Fredly H et al. The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia. Clin Epigenetics. 2013;5(1):13.CrossRefPubMedPubMedCentralGoogle Scholar
Kuendgen A et al. Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. Clin Epigenetics. 2011;2(2):389–99.CrossRefPubMedPubMedCentralGoogle Scholar
Brissot E, Mohty M. Which acute myeloid leukemia patients should be offered transplantation? Semin Hematol. 2015;52(3):223–31.CrossRefPubMedGoogle Scholar