Abstract
PurposeTo address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML).MethodsA xenograft AML mouse model was established by injecting HL-60 cells into tail vein of mice to assess the function of Curcumin. Mononuclear cells (MNCs) isolated from AML mice and AML cell lines were used to examine the effect of Curcumin. Metagenomics and metabolomics were used to evaluate the alteration of intestinal microbiota and the change of metabolites in MNCs.ResultsCurcumin treatment sensitized response to Ara-C in MNCs of AML mice, but had no direct effect on AML cell lines. Metagenomics revealed an alteration of intestinal microbiota with Curcumin treatment, which contributes to sensitized response to Ara-C. Curcumin treatment led to enhanced intestinal intact to sensitize response to Ara-C in AML mice, through reducing mucus degrading bacteria. Metabolomics demonstrated that Curcumin treatment led to decreased cholesterol in MNCs of AML mice. Further study proved that Curcumin treatment resulted in inhibition of SQLE, a key enzyme of cholesterol biosynthesis, to increase sensitivity to Ara-C.ConclusionCurcumin sensitizes response to Ara-C through regulating microbiota, highlighting the importance of intestinal intact strengthening in chemoresistant therapy. Moreover, aiming at cholesterol synthesis is promising in AML treatment.
Highlights
Acute myeloid leukemia (AML) originates from the differentiation block of myeloid cells in the bone marrow (BM) [1]
CCK-8 assay showed that Mononuclear cells (MNCs) isolated from Cur/A group displayed significantly reduced cell proliferation rate compared to phosphate-buffered saline (PBS)/A group (Fig. 1B)
Apoptosis assay revealed that Cur/A led to markedly increase of MNCs compared to the PBS + Ara-C (PBS/A) group (Fig. 1C)
Summary
Acute myeloid leukemia (AML) originates from the differentiation block of myeloid cells in the bone marrow (BM) [1]. Curcumin is a natural phenolic compound extracted from curcuma longa, which exerts a wide range of biological effects, such as anti-tumor, anti-inflammatory, anti-oxidation and anti-fibrosis [3, 4]. Curcumin was reported to affect energy metabolism to increase energy expenditure as well as improve insulin sensitivity in obese mice [5, 6]. Several studies have reported that targeting energy metabolism could sensitize resistant cells to chemotherapy, such as oxidative phosphorylation inhibitor redirected metabolism toward glycolysis to sensitize resistant cells to cytarabine (Ara-C) in AML [7]. Intestinal microbiota could enhance the effect of Curcumin in ameliorating HFDinduced obesity by enhancing Ucp1-dependent thermogenesis through regulating bile acids metabolism [8], suggesting the interaction between intestinal microbiota and Curcumin in curing diseases
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