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. 2020 Jan 15:14:185-194.
doi: 10.2147/DDDT.S228610. eCollection 2020.

Curcumin Combined with Thalidomide Reduces Expression of STAT3 and Bcl-xL, Leading to Apoptosis in Acute Myeloid Leukemia Cell Lines

Mahnaz Mohammadi Kian  1   2 , Mahdieh Salemi  1   2 , Mohammad Bahadoran  3 , Atousa Haghi  1   4 , Nasrin Dashti  5 , Saeed Mohammadi  1   2 , Shahrbano Rostami  1   2 , Bahram Chahardouli  1   2 , Davood Babakhani  1 , Mohsen Nikbakht  1   2
Affiliations

Curcumin Combined with Thalidomide Reduces Expression of STAT3 and Bcl-xL, Leading to Apoptosis in Acute Myeloid Leukemia Cell Lines

Mahnaz Mohammadi Kian et al. Drug Des Devel Ther. .

Abstract

Introduction: Acute myeloid leukemia (AML) is a type of blood disorder that exhibits uncontrolled growth and reduced ability to undergo apoptosis. Signal transducer and activator of transcription 3 (STAT3) is a family member of transcription factors which promotes carcinogenesis in most human cancers. This effect on AML is accomplished through deregulation of several critical genes, such as B cell lymphoma-extra-large (BCL-XL) which is anti-apoptotic protein. The aim of this study was to evaluate the effect of curcumin (CUR) and thalidomide (THAL) on apoptosis induction and also the alteration of the mRNA expression level of STAT3 and BCL-XL mRNA on AML cell line compounds.

Methods: The growth inhibitory effects of CUR and THAL and their combination were measured by MTT assay in U937 and KG-1 cell lines. The rates of apoptosis induction and cell cycle analysis were measured by concurrent staining with Annexin V and PI. The mRNA expression level of STAT3 and BCL-XL was evaluated by Real-Time PCR.

Results: CUR inhibited proliferation and induced apoptosis in both KG-1 and U937 cells and this effect increased by combination with THAL. The expression level of STAT3 and BCL-XL was significantly down-regulated in KG-1 cells after treatment by CUR and THAL and their combination.

Conclusion: Overall, our findings suggested that down-regulation of STAT3 and BCL-XL mRNA expression in response to CUR and THAL treatment lead to inhibition of cell growth and induction of apoptosis.

Keywords: Bcl-xL; STAT3; acute myeloid leukemia; curcumin; thalidomide.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic mechanisms of CUR/THAL on STAT3 and BCL-XL and contributing to carcinogenesis.
Figure 2
Figure 2
Effects of CUR and THAL on cell viability of KG-1 cell line evaluated by MTT assay. The anti-proliferative effects of THAL (0–100 μM), CUR (0–100 μM) in 24, 48 and 72 hrs and CUR/THAL in 24 and 48 hrs. Data are mean ± SE of three independent experiments. Statistical significances were defined at *P < 0.05 and **P < 0.01 compared to corresponding untreated controls.
Figure 3
Figure 3
Effects of CUR and THAL on cell viability of U937 cell line evaluated by MTT assay. The anti-proliferative effects of THAL (0–100 μM), CUR (0–100 μM) in 24, 48 and 72 hrs and CUR/THAL in 24 and 48 hrs. Data are mean ± SE of three independent experiments. Statistical significances were defined at *P < 0.05 and **P < 0.01 compared to corresponding untreated controls.
Figure 4
Figure 4
Flow Cytometry analysis. KG-1 cells treated with CUR (40 µM) and THAL (80 µM) and their combination. Necrosis and apoptosis effect of CUR and THAL and their combination in KG-1 cells after 48 hrs. Data are mean ± SE of three independent experiments. Statistical significance was defined at *P < 0.05 and **P < 0.01 compared to corresponding untreated controls.
Figure 5
Figure 5
Flow cytometry analysis. U937 cells treated with CUR (40 µM) and THAL (60 µM) and their combination. Necrosis and apoptosis effect of CUR and THAL and their combination in KG-1 cells after 48 hrs. Data mean ± SE of three independent experiments. Statistical significance was defined at *P < 0.05 and **P < 0.01 compared to corresponding untreated controls.
Figure 6
Figure 6
Cell cycle analysis. (A and B) 48 hrs exposure to different concentrations of CUR and THAL decreased the number of cells at G2 phase and increased the number of cells at sub G1 phase in KG-1 and U937 (all numbers presented as a percent). (C and D) Diagrams of cell cycle analysis in KG-1 and U937 cells. Our results showed changes in the proportion of cells at the G0/G1 phase of the cell cycle in KG-1 and U937 cells.
Figure 7
Figure 7
Examination of gene expression. (A) The effects of CUR and THAL on the mRNA expression level of STAT3 and BCL-XL in KG-1. (B) The effects of CUR and THAL on the mRNA expression level of STAT3 and BCL-XL in U937. Cells were determined by Real-Time PCR analysis. Values were normalized by the expression of the housekeeping gene (HPRT). Data are mean ± SE of three independent experiments. Statistical significance was defined at *P < 0.05 and **P < 0.01 compared to corresponding untreated controls.
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