| Background: Bcl-2 selective inhibitor venetoclax(ABT-199)can effectively and safely induce apoptosis in leukemia cells,but the clinical efficacy of single drugs is limited due to the inability to target other Bcl-2family proteins such as Mcl-1.The demethylating drug decitabine(DAC)can be used for elderly high-risk cytogenetic risk acute myeloid leukemia.Whether decitabine can enhance the antitumor effect of ABT-199 in TP53 mutant AML and improve drug resistance remains to be studied.Objective: To explore the anti-leukemia efficacy and molecular mechanism of decitabine combined with ABT-199 in TP53 mutant cells.Methods: Cell viability and proliferation were detected by CCK-8 and Ed U in three AML cell lines,THP-1 TP53-R248 Q,TP53-null and TP53-WT,and then drug sensitivity to decitabine and ABT-199 was also tested.In TP53-R248 Q and TP53-null,apoptosis was detected by flow cytometry,protein expression levels were detected by western blot and differentially expressed genes were analyzed by RNA-Seq technology to explore the antitumor effects and mechanisms of decitabine and ABT-199 alone and in combination.In a mouse model,the combined effect of decitabine and ABT-199 in vivo was verified by subcutaneous tumor formation in nude mice.Results:(1)Cell experiments demonstrated that TP53 mutation promoted AML cell growth and reduced sensitivity to ABT-199 and decitabine.(2)Both cell and nude mice experiments showed that decitabine could enhance the proliferation inhibition and apoptosis induction of ABT-199 on TP53 mutant AML cells.(3)Molecular mechanism revealed that decitabine may promote the degradation of antiapoptotic protein Mcl-1 and down-regulate its expression by downregulating m TOR/p-GSK3β-related pathway,and synergize with ABT-199 to exert an anti-tumor effect.Conclusion: In AML cells harboring TP53 mutations,decitabine exhibited synergistic antitumor effects with ABT-199 by downregulating the expression of the anti-apoptotic protein Mcl-1. |
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