Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

Abstract

Purpose To address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML). Methods A 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. Results Curcumin 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. Conclusion Curcumin 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.

A risk prediction model mediated by genes of APOD/APOC1/SQLE associates with prognosis in cervical cancer

“…APOC1 was reported as an oncogene to promote tumorigenesis and progression of glioblastoma [ 31 ], gastric cancer [ 32 ], hepatocellular carcinoma [ 33 ], breast cancer [ 34 ] and so on. SQLE is a key enzyme of cholesterol biosynthesis [ 35 ] and tends to be over-expressed along with treatment sensitivity in colon cancer [ 36 ], breast cancer and non-small cell lung cancer [ 37 ], Acute Myeloid Leukemia [ 38 ] and pancreatic cancer [ 39 ]. SQLE associates prognosis prediction of patients with bladder cancer [ 40 ].…”

Validation of a Mathematical Model Describing the Dynamics of Chemotherapy for Chronic Lymphocytic Leukemia In Vivo

“…On Day 22 after cell inoculation and prior to initiation of drug therapy, blood was taken from the tail vein of each mouse, and mCherry A20 cells were measured as described above. Drug treatment protocols using Cyt and Ibr were derived after comparing several published protocols in which these drugs had been used in in vivo studies (Cyt- [ 29 , 30 , 31 ]; Ibr- [ 32 , 33 , 34 ]). The 20 inoculated mice were randomly divided into 5 groups: Group 1: the Control group, which only received vehicle (PBS); Group 2: the Cyt Low group, which received 0.12 mg/kg of Cyt for 5 consecutive days; Group 3: the Cyt High group, which received 62.5 mg/kg of Cyt for 3 consecutive days; Group 4: the Ibr Low group, and Group 5: the Ibr High group, which received 9mg/kg and 18 mg/kg of Ibr, respectively, on days 1–5 and 8–10 from the beginning of the treatment.…”

“…Then, we conducted experiments in vivo to compare the cytotoxicity of two drugs—Cytarabine (Cyt), an inhibitor of the enzyme topoisomerase [ 28 ] and Ibr against the leukemic cells. The drug doses were selected by reviewing the literature on the use of these drugs in in vivo models of cancer [ 29 , 30 , 31 , 32 , 33 , 34 ]. The results afforded calculation of the killing rate of the A20 cells as a function of therapy.…”

Natural Inhibitors of P-glycoprotein in Acute Myeloid Leukemia

“…It has been documented, for example, that there is a bidirectional regulation between the curcumin, which implements the intestinal bacterial flora, and itself which can biotransform the curcumin. Furthermore, in studies using AML animal models, curcumin seems to sensitize the response to Ara-C (cytarabine) by regulating the microbiota and controlling the level of cholesterol, which improves chemoresistance [ 63 , 64 ].…”