Li J, Huang Y Q, Zi J, Song C H, Ge Z
Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, China.
Pennysvinia State University, College of Medicine and Hershey Medical Center, Hershey, PA 17033, USA Division of Hematology, The Ohio State University Wexner Medical Center and The James Cancer Hospital, Columbus, OH 43210, USA.
Zhonghua Xue Ye Xue Za Zhi. 2023 Dec 14;44(12):1001-1009. doi: 10.3760/cma.j.issn.0253-2727.2023.12.006.
This study aimed to explore the synergistic effect and underlying mechanism of azacitidine (AZA) in combination with homoharringtonine (HHT) in acute myeloid leukemia (AML) . 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. 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 (<0.001) and MV4-11 (<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. 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.
本研究旨在探讨阿扎胞苷（AZA）与高三尖杉酯碱（HHT）联合应用于急性髓系白血病（AML）的协同作用及潜在机制。通过细胞增殖、凋亡和集落形成试验检测AZA和HHT的协同作用。使用联合指数（CI）计算协同作用，并通过RNA测序、通路抑制剂和基因敲低方法探索潜在机制。与单药对照组相比，AZA和HHT联合应用显著诱导AML细胞的增殖停滞，且在AML细胞中显示出协同作用（CI < 0.9）。在联合用药组与单药对照组中，U937（<0.001）和MV4-11（<0.001）细胞的集落形成显著减少，而凋亡显著增加。AZA和HHT联合应用激活了整合应激反应（ISR）信号通路，并诱导细胞发生DDIT3-PUMA依赖的凋亡。此外，它还显著下调了c-MYC的表达。联合用药还激活了c-MYC/DDIT3/PUMA介导的ISR信号通路，从而在凋亡方面产生协同作用。AZA+HHT在凋亡方面的协同作用是通过激活c-MYC/DDIT3/PUMA介导的ISR信号通路诱导产生的。AZA和HHT联合应用通过抑制细胞增殖和通过c-MYC/DDIT3/PUMA轴激活ISR信号通路促进凋亡，发挥协同抗AML作用。
