SpringerLink
Log in

Low-Dose Triptolide Enhanced Activity of Idarubicin Against Acute Myeloid Leukemia Stem-like Cells Via Inhibiting DNA Damage Repair Response

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Leukemia stem cells (LSCs) are considered to be the root of relapse for acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eliminate LSCs. Therefore, new therapeutic strategies eliminating LSCs are urgently needed. Our results showed that low-dose Triptolide (TPL) enhanced the anti-AML activity of Idarubicin (IDA) in vitro against LSC-like cells (CD34 + CD38- KG1αand CD34 + CD38- kasumi-1 cells) and CD34+ primary AML cells, while sparing normal cells. Inspiringly, the combination treatment with low-dose TPL and IDA was also effective against CD34 + blasts from AML patients with FLT3-ITD mutation, which is an unfavorable risk factor for AML patients. Moreover, the combination of TPL and IDA induced a remarkable suppression of human leukemia growth in a xenograft mouse model. Mechanistically, the enhanced effect of low dose TPL on IDA against LSCs was attributed to inhibiting DNA damage repair response. Thus, our study may provide a theoretical basis to facilitate the development of a novel LSCs-targeting strategy for AML.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. De Kouchkovsky, I., & Abdul-Hay, M. (2016). Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer Journal, 6, e441.

    Article  Google Scholar 

  2. Daniel, T., & Ravindra, M. (2017). Biology and relevance of human acute myeloid leukemia stem cells. Blood, 129(12), 1577–1585.

    Article  Google Scholar 

  3. Kassim, A. A., & Savani, B. N. (2017). Hematopoietic stem cell transplantation for acute myeloid leukemia: A review. Hematology/Oncology and Stem Cell Therapy, 10, 245–251.

    Article  CAS  Google Scholar 

  4. Chatterjee, N., & Walker, G. C. (2017). Mechanisms of DNA damage, repair, and mutagenesis. Environmental and Molecular Mutagenesis, 58(5), 235–263.

    Article  CAS  Google Scholar 

  5. Woods, D., & Turchi, J. J. (2013). Chemotherapy induced DNA damage response. Cancer Biology & Therapy, 14(5), 379–389.

    Article  CAS  Google Scholar 

  6. Tian, H., Gao, Z., Li, H. Z., Zhang, B. F., Wang, G., Zhang, Q., et al. (2015). DNA damage response – A double-edged sword in cancer prevention and cancer therapy. Cancer Letters, 358, 8–16.

    Article  CAS  Google Scholar 

  7. Colomer, C., Margalef, P., Villanueva, A., Vert, A., Pecharroman, I., Solé, L., et al. (2019). IKKα kinase regulates the DNA damage response and drives chemo-resistance in cancer. Molecular Cell, 75(4), 669–682.e5.

    Article  CAS  Google Scholar 

  8. Biechonski, S., Yassin, M., & Milyavsky, M. (2017). DNA-damage response in hematopoietic stem cells: An evolutionary trade-off between blood regeneration and leukemia suppression. Carcinogenesis, 38(4), 367–377.

    Article  CAS  Google Scholar 

  9. Delia, D., & Mizutani, S. (2007). The DNA damage response pathway in normal hematopoiesis and malignancies. International Journal of Hematology, 106(3), 328–334.

    Article  Google Scholar 

  10. Dartsch, D. C., & Gieseler, F. (2007). Repair of idarubicin-induced DNA damage: A cause of resistance? DNA Repair, 6, 1618–1628.

    Article  CAS  Google Scholar 

  11. Li, H., Li, L., Mei, H., Pan, G., Wang, X., Huang, X., Wang, T., Jiang, Z., Zhang, L., & Sun, L. (2020). Antitumor properties of triptolide: Phenotype regulation of macrophage differentiation. Cancer Biology & Therapy, 21(2), 178–188.

    Article  CAS  Google Scholar 

  12. Noel, P., Von Hoff, D. D., Saluja, A. K., Velagapudi, M., Borazanci, E., & Han, H. (2019). Triptolide and its derivatives as cancer therapies. Trends in Pharmacological Sciences, 40(5), 327–341.

    Article  CAS  Google Scholar 

  13. Zhao, H., Shi, P., Deng, M., Jiang, Z., Li, Y., Kannappan, V., et al. (2016). Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption. Oncotarget, 7(51), 85515–85528.

    Article  Google Scholar 

  14. Huang, G., Hu, H., Zhang, Y., Zhu, Y., Liu, J., Tan, B., et al. (2019). Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT. Journal of Cancer, 10(13), 3012–3020.

    Article  CAS  Google Scholar 

  15. Chen, F., Liu, Y., Wang, S., Guo, X., Shi, P., Wang, W., et al. (2013). Triptolide, a Chinese herbal extract, enhances drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2. Pharmacogenomics, 14(11), 1305–1317.

    Article  CAS  Google Scholar 

  16. Yang, Q., Chen, K., Zhang, L., Feng, L., Fu, G., Jiang, S., Bi, S., Lin, C., Zhou, Y., Zhao, H., Chen, X. L., Fu, G., & Xu, B. (2019). Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway. Cancer Letters, 461, 31–43.

    Article  CAS  Google Scholar 

  17. Liu, Y., Chen, F., Wang, S., Guo, X., Shi, P., Wang, W., et al. (2013). Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors. Cell Death & Disease, 4, e948.

    Article  CAS  Google Scholar 

  18. Pollyea, D. A., & Jordan, C. T. (2017). Therapeutic targeting of acute myeloid leukemia stem cells. Blood, 129(12), 1627–1635.

    Article  CAS  Google Scholar 

  19. Bruserud, Ø., Aasebø, E., Hernandez-Valladares, M., Tsykunova, G., & Reikvam, H. (2017). Therapeutic targeting of leukemic stem cells in acute myeloid leukemia – The biological background for possible strategies. Expert Opinion on Drug Discovery, 12(10), 1053–1065.

    Article  Google Scholar 

  20. Shlush, L. I., Mitchell, A., Heisler, L., Abelson, S., Ng, S. W. K., Trotman-Grant, A., et al. (2017). Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature, 547, 104–108.

    Article  CAS  Google Scholar 

  21. Bernasconi, P., & Borsani, O. (2019). Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment. Journal of Oncology, 2019, 8323592.

    Article  Google Scholar 

  22. Hosokawa, M., Tanaka, S., Ueda, K., Iwakawa, S., & Ogawara, K. I. (2019). Decitabine exerted synergistic effects with oxaliplatin in colorectal cancer cells with intrinsic resistance to decitabine. Biochemical and Biophysical Research Communications, 509(1), 249–254.

    Article  CAS  Google Scholar 

  23. Lyu, M., Liao, H., Shuai, X., **, Y., Su, J., & Zheng, Q. (2020). The prognosis predictive value of FMS-like tyrosine kinase 3-internal tandem duplications mutant allelic ratio (FLT3-ITD MR) in patients with acute myeloid leukemia detected by GeneScan. Gene, 726, 144195. https://doi.org/10.1016/j.gene.2019.144195.

    Article  CAS  PubMed  Google Scholar 

  24. Pratz, K., Rudek, M., Smith, B., Karp, J., Gojo, I., Dezern, A., Jones, R., Greer, J., Gocke, C., Baer, M., Duong, V., Rosner, G., Zahurak, M., Wright, J., Emadi, A., & Levis, M. (2019). A prospective study of peri-transplant sorafenib for FLT3-ITD AML patients undergoing allogeneic transplantation. Biology of Blood and Marrow Transplantation, 26, 300–306. https://doi.org/10.1016/j.bbmt.2019.09.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, C., Lam, S., Leung, G., Tsui, S.-P., Yang, N., Ng, N., et al. (2019). Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3. Cancer., 126, 344–353. https://doi.org/10.1002/cncr.32534.

    Article  CAS  PubMed  Google Scholar 

  26. Beeharry, N., Landrette, S., Gayle, S., Hernandez, M., Grotzke, J. E., Young, P. R., et al. (2019). LAM-003, a new drug for treatment of tyrosine kinase inhibitor-resistant FLT3-ITD-positive AML. Blood Advances, 3(22), 3661–3673.

    Article  Google Scholar 

  27. Moloney, J. N., & Cotter, T. G. (2018). ROS signalling in the biology of cancer. Seminars in Cell & Developmental Biology, 80, 50–64.

    Article  CAS  Google Scholar 

  28. Hong, M., Li, J., Li, S., & Almutairi, M. M. (2019). Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation. Cells, 8(11), 1466.

    Article  CAS  Google Scholar 

  29. Hosoya, N., & Miyagawa, K. (2014). Targeting DNA damage response in cancer therapy. Cancer Science, 105, 370–388.

    Article  CAS  Google Scholar 

  30. Das, S., Camphausen, K., & Shankavaram, U. (2019). Pan-cancer analysis of potential synthetic lethal drug targets specific to alterations in DNA damage response. Frontiers in Oncology, 9, 1136.

    Article  Google Scholar 

  31. Ma, M., Rodriguez, A., & Sugimoto, K. (2019). Activation of ATR-related protein kinase upon DNA damage recognition. Current Genetics, 66, 327–333.

    Article  Google Scholar 

  32. Rothkamm, K., Barnard, S., Moquet, J., Ellender, M., Rana, Z., & Burdak-Rothkamm, S. (2015). DNA damage foci: Meaning and significance. Environmental and Molecular Mutagenesis, 56(6), 491–504.

    Article  CAS  Google Scholar 

  33. Zhang, Y., & Hunter, T. (2014). Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer, 134(5), 1013–1023.

    Article  CAS  Google Scholar 

  34. Luo, Q., Guo, H., Kuang, P., Cui, H., Deng, H., Liu, H., Lu, Y., Wei, Q., Chen, L., Fang, J., Zuo, Z., Deng, J., Li, Y., Wang, X., & Zhao, L. (2018). Sodium fluoride arrests renal G2/M phase cell-cycle progression by activating ATM-Chk2-P53/Cdc25C signaling pathway in mice. Cellular Physiology and Biochemistry, 51, 2421–2433. https://doi.org/10.1159/000495899.

    Article  CAS  PubMed  Google Scholar 

Download references

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This work was financially supported by National Nature Science Foundation of China, PR China (Grant No.81570156, No.81570425, No. 81770126 and N0. 81700156). Prof. Pengcheng Shi, Young Scientists Fund (No. 81700156). Prof. Bing Xu, National Natural Science Foundation of China (No.81570156, No.81570425, No. 81770126).

Author information

Author notes

  1. Pengcheng Shi, Jie Zha and Juan Feng contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Pengcheng Shi & Naying Liao

  2. Department of Hematology, The First Affiliated Hospital of **amen University and Institute of Hematology, School of Medicine, **amen University, No.55, Zhenhai Road, **amen, Fujian, 361003, People’s Republic of China

    Jie Zha, Juan Feng, Haijun Zhao, Manman Deng & Bing Xu

  3. Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China

    Zhiwu Jiang & Peng Li

  4. Department of Hematology, Affiliated Dongguan People’s Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, 523059, People’s Republic of China

    Yirong Jiang

  5. Department of Immunology, DICAT Biomedical Computation Centre, Vancouver, BC, Canada

    Haihan Song

Authors
  1. Pengcheng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiwu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haijun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manman Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naying Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yirong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haihan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: Pengcheng Shi, Jie Zha, Juan Feng, Yirong Jiang, Haihan Song, Bing Xu. Acquisition, analysis and interpretation of data: Pengcheng Shi, Jie Zha, Juan Feng, Bing Xu. Development of methodology: Pengcheng Shi, Jie Zha, Juan Feng, Zhiwu Jiang, Haijun Zhao. Primary samples collection and purification and validation: Pengcheng Shi, Manman Deng, Naying Liao. Animal model analysis and data collection: Pengcheng Shi, Zhiwu Jiang, Peng Li. Writing, and revision of the manuscript: Pengcheng Shi, Jie Zha, Juan Feng, Yirong Jiang, Haihan Song, Bing Xu. Supplemental experiments: Pengchengshi and Jie zha. Response to reviewers: Pengchengshi, Jiezha and Bing Xu.

Corresponding authors

Correspondence to Yirong Jiang, Haihan Song or Bing Xu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

This study was carried out in accordance with the Declaration of Helsinki, and approved by the Ethics Review Board of Nanfang Hospital.

Consent to Participate

Bone marrow aspirates of AML patients and peripheral blood of healthy donors were obtained with the informed consent for research purposes.

Consent to Publish

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 25 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, P., Zha, J., Feng, J. et al. Low-Dose Triptolide Enhanced Activity of Idarubicin Against Acute Myeloid Leukemia Stem-like Cells Via Inhibiting DNA Damage Repair Response. Stem Cell Rev and Rep 17, 616–627 (2021). https://doi.org/10.1007/s12015-020-10054-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-020-10054-1

Keywords

Search

Navigation