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Rapamycin increases leukemia cell sensitivity to chemotherapy by regulating mTORC1 pathway-mediated apoptosis and autophagy

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Abstract

This study investigated the effect of rapamycin alone and in combination with chemotherapy (doxorubicin and cytarabine) on AML. Human acute monocytic leukemia cell line SHI-1 and NPG AML model mice created by intravenous injection of SHI-1 cell were treated with rapamycin, chemotherapy, or rapamycin plus chemotherapy. Analysis by cell counting kit-8, western blot, flow cytometry, and immunohistochemistry was performed, and results suggested that both rapamycin and chemotherapy inhibited proliferation of SHI-1 cells both in vitro and in vivo, suppressed neoplasm growth in vivo, and promoted survival of NPG AML mice. The antitumor effect of rapamycin plus chemotherapy was better than that of rapamycin alone and chemotherapy alone. In addition, western blot results demonstrated that rapamycin inhibited the phosphorylation of mTOR downstream targets 4EBP1 and S6K1 in SHI-1 cells, and increased the pro-apoptosis-related protein Bax and autophagy-associated proteins Beclin-1, LC3B-II, and ATG5 while reducing the anti-apoptosis-related protein Bcl-2. In conclusion, the results of this study indicate that rapamycin acts synergistically with doxorubicin and cytarabine in AML treatment, and its underlying mechanism might be associated with mTORC1 pathway-mediated apoptosis and autophagy.

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All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Funding

This study was supported by the National Natural Science Foundation of China (82260037) and Jiangxi “5511” Science and Technology Innovation Talent Project (Grant No. 20171BCB18003).

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Authors and Affiliations

  1. Department of Hematology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, China

    Jing Xu, Jifu Zheng, Qingming Wang, Aiping Tang, Yuan Song, Yan Fei & Zhenjiang Li

  2. Second Clinical Medical College, Nanchang University, Nanchang, 330006, China

    Siwen Zong

  3. Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China

    Tianle Sheng & Qiong Wu

Authors
  1. Jing Xu
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  2. Siwen Zong
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  3. Tianle Sheng
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  4. Jifu Zheng
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  5. Qiong Wu
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  6. Qingming Wang
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  8. Yuan Song
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  9. Yan Fei
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  10. Zhenjiang Li
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Contributions

J.X. and Z.J.L. designed the study. J.X., S.Z., T.S., J.F.Z., Q.W., and Q.M.W. preformed the experiment. J.X., S.Z., T.S., A.P.T., Y.S., and Y.F. analyzed the data. J.X. drafted the manuscript. Z.J.L. supervised the study and revised the manuscript.

Corresponding author

Correspondence to Zhenjiang Li.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

All the animal experiment protocols were approved by the Ethics Committee of the Nanchang Royo Biotech Co,. Ltd (Approve number: RYE2018030601), and all methods were followed in accordance with the approved guidelines.

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Xu, J., Zong, S., Sheng, T. et al. Rapamycin increases leukemia cell sensitivity to chemotherapy by regulating mTORC1 pathway-mediated apoptosis and autophagy. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03732-0

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