Open Access

Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle

  • Authors:
    • Xiaobo Wang
    • Lihua Yuan
    • Bo Lu
    • Dongjun Lin
    • Xiaojun Xu
  • View Affiliations

  • Published online on: October 26, 2023     https://doi.org/10.3892/etm.2023.12274
  • Article Number: 574
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome‑refractory anemia with excess blast‑1 and ‑2 (MDS‑RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL‑2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL‑1) in acute myeloid leukemia cells. MCL‑1 is an anti‑apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM‑1 cell lines were treated in vitro with 0‑2 µM venetoclax and 0‑4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography‑mass spectrometry (α‑KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine‑serine‑cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome‑refractory anemia cell line at lower concentrations.
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December-2023
Volume 26 Issue 6

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Spandidos Publications style
Wang X, Yuan L, Lu B, Lin D and Xu X: Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle. Exp Ther Med 26: 574, 2023
APA
Wang, X., Yuan, L., Lu, B., Lin, D., & Xu, X. (2023). Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle. Experimental and Therapeutic Medicine, 26, 574. https://doi.org/10.3892/etm.2023.12274
MLA
Wang, X., Yuan, L., Lu, B., Lin, D., Xu, X."Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle". Experimental and Therapeutic Medicine 26.6 (2023): 574.
Chicago
Wang, X., Yuan, L., Lu, B., Lin, D., Xu, X."Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle". Experimental and Therapeutic Medicine 26, no. 6 (2023): 574. https://doi.org/10.3892/etm.2023.12274