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. 2024 Jan 1;25(1):343-350.
doi: 10.31557/APJCP.2024.25.1.343.

The Effects of ABT-199 and Dihydroartemisinin Combination on Cell Growth and Apoptosis in Human U937 and KG-1 Cancer Cells

Roya Nazmabadi  1 , Marziyeh Pooladi  1   2 , Jamal Amri  3 , Marayam Darvish  1 , Yusef Abbasi  4 , Hadi Karami  1
Affiliations

The Effects of ABT-199 and Dihydroartemisinin Combination on Cell Growth and Apoptosis in Human U937 and KG-1 Cancer Cells

Roya Nazmabadi et al. Asian Pac J Cancer Prev. .

Abstract

Introduction: Change in the balance of Bcl-2 family proteins is one of the main reasons for resistance of tumor cells to ABT-199. In this study, the effect of dihydroartemisinin on cell growth, apoptosis and sensitivity of the AML cells to ABT-199 was investigated.

Methods: Cell proliferation and survival were assessed by trypan blue staining and MTT assay, respectively. Cell apoptosis was measured by Hoechst 33342 staining and caspase-3 activity assay. The expression levels of Bcl-2, Mcl-1 and Bax mRNA were tested by qRT-PCR.

Results: Our data showed that combination therapy significantly reduced the IC50 value and synergistically decreased the AML cell survival and growth compared with dihydroartemisinin or ABT-199 alone. Treatment with each of ABT-199 or dihydroartemisinin alone clearly enhanced the Bax mRNA expression and inhibited the expression of Mcl-1 and Bcl-2 mRNA. Inhibition of Mcl-1 mRNA by dihydroartemisinin was associated with enhancement of apoptosis induced by ABT-199 in AML cells.

Conclusion: In conclusion, dihydroartemisinin not only triggers the intrinsic pathway of apoptosis, but also can increase the sensitivity of the AML cells to ABT-199 via suppression of Mcl-1 expression.

Keywords: ABT-199; AML; Apoptosis; Bcl-2; dihydroartemisinin.

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Conflict of interest statement

The authors have no conflict of interest to declare

Figures

Figure 1
Figure 1
Effect of Dihydroartemisinin and ABT-199 Combination on Cell Survival. The U937 and KG-1 cells were exposed to dihydroartemisinin (DHA) (A) and ABT-199 (B) at indicated concentrations. After 24 h, the cell survival rate was measured using MTT assay. The cell survival curves were plotted using GraphPad 6.1 software (C, D, F and G). Data are showed as mean±SD of three experiments. The combination index (CI) values were determined using the fractional affected (Fa) values of MTT assay and CalcuSyn software (E and H).
Figure 2
Figure 2
Proliferation Inhibition of AML Cells. The U937 and KG-1 cells were treated with ABT-199 and dihydroartemisinin (DHA) for 1-5 day. Next, the cell viability was determined using trypan blue exclusion assay. The data are showed as mean±SD of three experiments. *p<0.05 versus blank control or solvent control
Figure 3
Figure 3
RT-qPCR Analysis of AML Cells. The U937 and KG-1 cells were treated with dihydroartemisinin (DHA) and ABT-199 (IC50 doses) for 24 h. Next, relative mRNA expression levels of Bcl-2 (A and D), Mcl-1 (B and E) and Bax (C and F) were determined by RT-qPCR using 2-(∆∆Ct) method. Results are presented as mean±SD (n=3). #p< 0.05 relative to single treatment; *p<0.05 relative to blank control
Figure 4
Figure 4
The Effect of Dihydroartemisinin and ABT-199 on Apoptosis of AML Cells. U937 and KG-1 cells were exposed to the IC50 doses of dihydroartemisinin (DHA) and ABT-199 for 24 h. Next, the apoptosis was measured using Hoechst 33342 staining (A and B) and caspase-3 activity assay (C and D). The data are expressed as mean±SD (n=3) of three experiments. *p<0.05 compared with blank control. Arrows show the apoptotic cells
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