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Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

ABSTRACT: PURPOSE:Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFN?) in various cancers. Therefore, we examined IFN? and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics. METHODS:The anti-leukemic effects of IFN? and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFN?-2b and human IFN?-Le in MOLM-13 cells by IMAC/2D DIGE/MS analysis and phospho-flow cytometry, and in primary healthy and AML patient-derived PBMCs by CyTOF. In vivo, IFN?-Le and VPA efficacy were investigated in the immunodeficient NOD/Scid IL2?-/- MOLM-13Luc+ mouse model and the syngeneic immunocompetent BNML rat model. RESULTS:IFN?-2b and IFN?-Le differed in the modulation of phospho-proteins involved in protein folding, cell stress, cell death and p-STAT6 Y641, whereas VPA and IFN?-Le shared signaling pathways involving phosphorylation of Akt (T308), ERK1/2 (T202/T204), p38 (T180/Y182), and p53 (S15). Both IFN? compounds induced apoptosis synergistically with VPA in vitro. However, in vivo, VPA monotherapy increased survival, but no benefit was observed by IFN?-Le treatment. CyTOF analysis of primary human PBMCs indicated that lack of immune-cell activation could be a reason for the absence of response to IFN? in the animal models investigated. CONCLUSIONS:IFN?-2b and IFN?-Le showed potent and synergistic anti-leukemic effects with VPA in vitro but not in leukemic mouse and rat models in vivo. The absence of IFN? immune activation in lymphocyte subsets may potentially explain the limited in vivo anti-leukemic effect of IFN?-monotherapy in AML.

SUBMITTER: Forthun RB

PROVIDER: S-EPMC6571093 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

Forthun Rakel Brendsdal RB Hellesøy Monica M Sulen André A Kopperud Reidun Kristin RK Sjøholt Gry G Bruserud Øystein Ø McCormack Emmet E Gjertsen Bjørn Tore BT

Journal of cancer research and clinical oncology 20190520 7

<h4>Purpose</h4>Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics.<h4>Methods</h4>The anti-leukemic effects of IFNα and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFNα-2b and human IFNα-L ...[more]

PMID: 31111215

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Project description:A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.In this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.The study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.Treatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.

Dataset Information

Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

Publications

Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

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