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Biomodulatory Treatment With Azacitidine, All-trans Retinoic Acid and Pioglitazone Induces Differentiation of Primary AML Blasts Into Neutrophil Like Cells Capable of ROS Production and Phagocytosis.

ABSTRACT: Effective and tolerable salvage therapies for elderly patients with chemorefractory acute myeloid leukemia (AML) are limited and usually do not change the poor clinical outcome. We recently described in several chemorefractory elderly AML patients that a novel biomodulatory treatment regimen consisting of low-dose azacitidine (AZA) in combination with PPAR? agonist pioglitazone (PGZ) and all-trans retinoic acid (ATRA) induced complete remission of leukemia and also triggered myeloid differentiation with rapid increase of peripheral blood neutrophils. Herein, we further investigated our observations and comprehensively analyzed cell differentiation in primary AML blasts after treatment with ATRA, AZA, and PGZ ex vivo. The drug combination was found to significantly inhibit cell growth as well as to induce cell differentiation in about half of primary AML blasts samples independent of leukemia subtype. Notably and in comparison to ATRA/AZA/PGZ triple-treatment, effects on cell growth and myeloid differentiation with ATRA monotherapy was much less efficient. Morphological signs of myeloid cell differentiation were further confirmed on a functional basis by demonstrating increased production of reactive oxygen species as well as enhanced phagocytic activity in AML blasts treated with ATRA/AZA/PGZ. In conclusion, we show that biomodulatory treatment with ATRA/AZA/PGZ can induce phenotypical and functional differentiation of primary AML blasts into neutrophil like cells, which aside from its antileukemic activity may lower neutropenia associated infection rates in elderly AML patients in vivo. Clinical impact of the ATRA/AZA/PGZ treatment regimen is currently further investigated in a randomized clinical trial in chemorefractory AML patients (NCT02942758).

SUBMITTER: Klobuch S

PROVIDER: S-EPMC6278634 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:Acute lung injury (ALI) is a common clinical emergency and all‑trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)‑induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO2), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit‑8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll‑like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)‑65, p65, p‑IκBα and IκBα were analyzed using western blotting. The concentrations of IL‑6, IL‑1β and macrophage inflammatory protein‑2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO‑102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS‑induced ALI, as evidenced by the increased PaO2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF‑κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4‑NF‑κB pathway in LPS‑induced ALI. In summary, ATRA inactivated the NF‑κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI.

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Biomodulatory Treatment With Azacitidine, All-trans Retinoic Acid and Pioglitazone Induces Differentiation of Primary AML Blasts Into Neutrophil Like Cells Capable of ROS Production and Phagocytosis.

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