curcumin and Myelodysplastic-Syndromes

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of

Topics: Animals; Curcumin; Disease-Free Survival; DNA-Binding Proteins; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Heme; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Myelodysplastic Syndromes; Promoter Regions, Genetic; Transcription Factors

Azacitidine (AZA) is a hypomethylating agent used in myeloid neoplasms, however, approximately half of patients show treatment failure or relapse. This in vitro study investigated the effect of the combination of AZA with the natural compound curcumin (CUR) in increasing its efficacy.. We analyzed the effects of AZA plus CUR on proliferation, apoptosis, cell cycle and differentiation in myeloid leukemic cell lines (U-937, HL-60, K-562, and OCI-AML3) and bone marrow samples of patients.. The results showed a synergy between AZA and CUR in all leukemic lines and in most leukemic samples, with a decrease in proliferation and an increase in apoptosis compared to the activity of each drug separately. In addition, AZA plus CUR showed low cytotoxicity in healthy samples.. A remarkable antioncogenic effect of the combination of AZA plus CUR was shown, providing a basis for future studies analyzing the clinical efficacy of these drugs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Azacitidine; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Curcumin; Drug Synergism; Female; Humans; Leukemia, Myeloid; Male; Myelodysplastic Syndromes

Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase that regulates histone H3 methylation of lysine27 (H3K27me3), is involved in the pathogenesis of myelodysplastic syndrome (MDS). Targeting epigenetic regulators has been identified as a potential treatment target in MDS chemotherapy. Curcumin, a natural compound extracted from turmeric, was found to possess a wide range of anticancer activities in various tumors.. This study was designed to investigate the inhibitory effect and action mechanism of curcumin in myelodysplastic syndrome (MDS) in vitro and in vivo.. Our results showed that curcumin can significantly suppress cell proliferation and induce cell apoptosis and cell cycle arrest in human MDS-derived cell lines. It reduced EZH2, DNA methyltransferase 3A (DNMT3a), ASXL1 and downstream H3K4me3, H3K27me3 and HOXA9 expression and inhibited EZH2 and H3K27me3 nuclear translocation. Curcumin also showed anti-cancer effects in a xenograft mouse model and reduced EZH2, H3K4me3 and H3K27me3 in vivo. EZH2 knockdown can reduce the H3K27me3 levels and induce curcumin resistance in vitro but attenuates leukemic transformation in vivo.. These findings provide the potential molecular mechanism of curcumin as a therapeutic agent for MDS.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; DNA Methylation; DNA Methyltransferase 3A; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myelodysplastic Syndromes; Xenograft Model Antitumor Assays

Low response, treatment-related complications and relapse due to the low sensitivity of myelodysplastic syndrome (MDS) and leukemia stem cells (LSCs) or pre‑LSCs to arsenic trioxide (ATO), represent the main problems following treatment with ATO alone in patients with MDS. To solve these problems, a chemosensitization agent can be applied to increase the susceptibility of these cells to ATO. Curcumin (CUR), which possesses a wide range of anticancer activities, is a commonly used chemosensitization agent for various types of tumors, including hematopoietic malignancies. In the present study, we investigated the cytotoxic effects and potential mechanisms in MDS-SKM-1 and leukemia stem-like KG1a cells treated with CUR and ATO alone or in combination. CUR and ATO exhibited growth inhibition detected by MTT assays and apoptosis analyzed by Annexin V/PI analyses in both SKM-1 and KG1a cells. Apoptosis of SKM-1 and KG1a cells determined by Annexin V/PI was significantly enhanced in the combination groups compared with the groups treated with either agent alone. Further evaluation was performed by western blotting for two hallmark markers of apoptosis, caspase-3 and cleaved-PARP. Co-treatment of the cells with CUR and ATO resulted in significant synergistic effects. In SKM-1 and KG1a cells, 31 and 13 proteins analyzed by protein array assays were modulated, respectively. Notably, survivin protein expression levels were downregulated in both cell lines treated with CUR alone and in combination with ATO, particularly in the latter case. Susceptibility to apoptosis was significantly increased in SKM-1 and KG1a cells treated with siRNA-survivin and ATO. These results suggested that CUR increased the sensitivity of SKM-1 and KG1a cells to ATO by downregulating the expression of survivin.

Topics: Apoptosis; Arsenic Trioxide; Arsenicals; Caspase 3; Cell Line, Tumor; Curcumin; Down-Regulation; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Leukemia; Myelodysplastic Syndromes; Oxides; Poly(ADP-ribose) Polymerases; RNA, Small Interfering; Stem Cells; Survivin