Homoharringtonine synergy with oridonin in treatment of t(8; 21) acute myeloid leukemia

Abstract

Collaboration of c-KIT mutations with AML1–ETO (AE) has been demonstrated to induce t(8; 21) acute myeloid leukemia (AML). Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8; 21) AML. Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations, whereas oridonin can induce t(8; 21) AML cell apoptosis and AE cleavage. Therefore, studies should explore the efficacy of combination therapy with oridonin and HHT in t(8; 21) AML. In this study, we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8; 21) AML cell line and mouse model. The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis. Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage. HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1, thus enhancing the effects of oridonin. The combination of oridonin and HHT prolonged t(8; 21) leukemia mouse survival. In conclusion, oridonin and HHT exert synergistic effects against t(8; 21) leukemia in vivo and in vitro, thereby indicating that their combination may be an effective therapy for t(8; 21) leukemia.

Keywords

AML1–ETO / c-KIT / homoharringtonine / oridonin / t(8 / 21) AML / synergistic effect

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Acknowledgements

This work was supported by the Mega Projects of Scientific Research for the 12th Five-Year Plan (No. 2013ZX09102001), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (No. 20152507), Tang Scholar (No. 2017), and the Innovation Foundation for Doctoral Student of Shanghai Jiao Tong University School of Medicine (No. 2014282).

Compliance with ethics guidelines

Weina Zhang, Ying Lu, Tao Zhen, Xinjie Chen, Ming Zhang, Ping Liu, Xiangqin Weng, Bing Chen, and Yueying Wang declare no competing interests. All animal experiments were conducted in accordance with the ethical guidelines on animal care of our institution and were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University School of Medicine.

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