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

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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 HHTexert 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.

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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).

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Authors and Affiliations

  1. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Weina Zhang, Ying Lu, Tao Zhen, Xinjie Chen, Ming Zhang, Ping Liu, Xiangqin Weng, Bing Chen & Yueying Wang

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  1. Weina Zhang
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  2. Ying Lu
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  3. Tao Zhen
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  4. Xinjie Chen
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  5. Ming Zhang
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  7. Xiangqin Weng
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  8. Bing Chen
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  9. Yueying Wang
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Correspondence to Yueying Wang.

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Zhang, W., Lu, Y., Zhen, T. et al. Homoharringtonine synergy with oridonin in treatment of t(8; 21) acute myeloid leukemia. Front. Med. 13, 388–397 (2019). https://doi.org/10.1007/s11684-018-0624-1

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  • DOI: https://doi.org/10.1007/s11684-018-0624-1

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