Synergistic effect of azacitidine with homoharringtonine by activating the c-MYC/DDIT3/PUMA axis in acute myeloid leukemia
10.3760/cma.j.issn.0253-2727.2023.12.006
- VernacularTitle:阿扎胞苷联合高三尖杉酯碱通过调控c-MYC/DDIT3/PUMA轴协同抗急性髓系白血病的研究
- Author:
Jun LI
1
;
Yanqing HUANG
;
Jie ZI
;
Chunhua SONG
;
Zheng GE
Author Information
1. 东南大学附属中大医院血液科，东南大学血液病研究所，南京 210009
- Keywords:
Azacitidine;
Homoharringtonine;
Leukemia, myeloid, acute;
Synergistic effect
- From:
Chinese Journal of Hematology
2023;44(12):1001-1009
- CountryChina
- Language:Chinese
-
Abstract:
Objective:This study aimed to explore the synergistic effect and underlying mechanism of azacitidine (AZA) in combination with homoharringtonine (HHT) in acute myeloid leukemia (AML) .Methods:The synergistic effects of AZA and HHT were examined by cell proliferation, apoptosis, and colony formation assays. The synergistic effects were calculated using the combination index (CI) , and the underlying mechanisms were explored using RNA sequencing, pathway inhibitors, and gene knockdown approaches.Results:Compared with the single-drug controls, AZA and HHT combination significantly induced cell proliferation arrest and showed a synergistic effect with CI < 0.9 in AML cells. In the combination group versus the single-drug controls, colony formation was significantly decreased, whereas apoptosis was significantly increased in U937 ( P<0.001) and MV4-11 ( P<0.001) cells. AZA and HHT combination activated the integrated stress response (ISR) signaling pathway and induced DDIT3-PUMA-dependent apoptosis in cells. Furthermore, it remarkably downregulated the expression of c-MYC. The combination also activated c-MYC/DDIT3/PUMA-mediated ISR signaling to induce synergy on apoptosis. The synergy of AZA+HHT on apoptosis was induced by activating c-MYC/DDIT3/PUMA-mediated ISR signaling. Conclusion:The combination of AZA and HHT exerts synergistic anti-AML effects by inhibiting cellular proliferation and promoting apoptosis through activation of the ISR signaling pathway via the c-MYC/DDIT3/PUMA axis.
