Skip to main content

Advertisement

SpringerLink
Log in

A promising natural product in diffuse large B-cell lymphoma therapy by targeting PIM1

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of B-cell lymphoma. Unfortunately, about one-third of patients either relapse after the initial treatment or are refractory to first-line therapy, indicating a need for new treatment modalities. PIM serine/threonine kinases are proteins that are associated with genetic mutations, overexpression, or translocation events in B-cell lymphomas. We conducted an integrative analysis of whole-exome sequencing in 52 DLBCL patients, and no amplification, mutation, or translocation of the PIM1 gene was detected. Instead, analyses of TCGA and GTEx databases identified that PIM1 expression was increased in DLBCL samples compared to normal tissue, and high expression levels were associated with poor overall survival. Moreover, interference of PIM1 significantly suppressed DLBCL cell proliferation. In addition, we identified anwulignan, a natural small-molecule compound, as a PIM1 inhibitor. Anwulignan directly binds to PIM1 and exerts antitumor effects on DLBCL in vitro and in vivo by inducing apoptosis, cell cycle arrest, and autophagic cell death. Furthermore, we identified an effective synergistic combination between anwulignan and chidamide. Our findings suggested that PIM1 could be a therapeutic target and prognostic factor for DLBCL, and anwulignan holds promise for future development as a natural product for treatment.

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

Access this article

Log in via an institution

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
Fig. 6

Similar content being viewed by others

Data availability

The data supporting the findings of this study can be found in the article or available from the corresponding author upon reasonable request.

References

  1. Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503–511

    Article  CAS  PubMed  ADS  Google Scholar 

  2. Chen H, Qin Y, Liu P et al (2023) Genetic profiling of diffuse large B-cell lymphoma: a comparison between double-expressor lymphoma and non-double-expressor lymphoma. Mol Diagn Ther 27(1):75–86

    Article  CAS  PubMed  Google Scholar 

  3. Wang L, Li LR (2020) R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms. Chin Med J (Engl) 134(3):253–260

    Article  PubMed  Google Scholar 

  4. Panchal NK, Sabina EP (2020) A serine/threonine protein PIM kinase as a biomarker of cancer and a target for anti-tumor therapy. Life Sci 255:117866

    Article  CAS  PubMed  Google Scholar 

  5. Szydłowski M, Prochorec-Sobieszek M, Szumera-Ciećkiewicz A et al (2017) Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma. Blood 130(12):1418–1429

    Article  PubMed  Google Scholar 

  6. Chen LS, Redkar S, Bearss D, Wierda WG, Gandhi V (2009) Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood 114(19):4150–4157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Szydłowski M, Garbicz F, Jabłońska E et al (2021) Inhibition of PIM Kinases in DLBCL targets MYC transcriptional program and augments the efficacy of anti-CD20 antibodies. Cancer Res 81(23):6029–6043

    Article  PubMed  Google Scholar 

  8. Spradlin JN, Hu X, Ward CC et al (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat Chem Biol 15(7):747–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yarla NS, Bishayee A, Sethi G et al (2016) Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 40–41:48–81

    Article  PubMed  Google Scholar 

  10. Kampan NC, Madondo MT, McNally OM, Quinn M, Plebanski M (2015) Paclitaxel and its evolving role in the management of ovarian cancer. Biomed Res Int 2015:413076

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hartert KT, Wenzl K, Krull JE et al (2021) Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL. Leukemia 35(2):522–533

    Article  CAS  PubMed  Google Scholar 

  12. Lu Y, Chen DF (2009) Analysis of Schisandra chinensis and Schisandra sphenanthera. J Chromatogr A 1216(11):1980–1990

    Article  CAS  PubMed  Google Scholar 

  13. Horiuchi D, Camarda R, Zhou AY et al (2016) PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 22(11):1321–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y, Wang Z, Li X, Magnuson NS (2008) Pim kinase-dependent inhibition of c-Myc degradation. Oncogene 27(35):4809–4819

    Article  CAS  PubMed  Google Scholar 

  15. Kim YC, Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125(1):25–32

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kabeya Y, Mizushima N, Ueno T et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J 19(21):5720–5728

  17. Colli LM, Machiela MJ, Zhang H et al (2017) Landscape of combination immunotherapy and targeted therapy to improve cancer management. Cancer Res 77(13):3666–3671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Poletto S, Novo M, Paruzzo L, Frascione PMM, Vitolo U (2022) Treatment strategies for patients with diffuse large B-cell lymphoma. Cancer Treat Rev 110:102443

    Article  CAS  PubMed  Google Scholar 

  19. Xie X, Wang X, Shi X et al (2021) Anwulignan is a novel JAK1 inhibitor that suppresses non-small cell lung cancer growth. J Cell Mol Med 25(5):2645–2654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Skrott Z, Mistrik M, Andersen KK et al (2017) Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552(7684):194–199

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  21. Ross NT, Lohmann F, Carbonneau S et al (2020) CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma. Nat Chem Biol 16(1):50–59

    Article  CAS  PubMed  Google Scholar 

  22. Buettner R, Morales C, Caserta E et al (2019) Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting. Blood Adv 3(7):1027–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kreuz S, Holmes KB, Tooze RM, Lefevre PF (2015) Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. Mol Cancer 14:205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gu S, Hou Y, Dovat K, Dovat S, Song C, Ge Z (2023) Synergistic effect of HDAC inhibitor chidamide with cladribine on cell cycle arrest and apoptosis by targeting HDAC2/c-Myc/RCC1 axis in acute myeloid leukemia. Exp Hematol Oncol 12(1):23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Luo C, Yu T, Young KH, Yu L (2022) HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression. J Zhejiang Univ Sci B 23(8):666–681

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of China (82270197, 82270211), The special project of “Technological innovation” project of CNNC Medical Industry Co. Ltd (ZHYLYB2021002), Natural Science Foundation of Jiangsu Province China (BK20201408).

Author information

Authors and Affiliations

  1. Department of Hematology, the Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, 215006, China

    Xinyun Zhang, Yuchen Zhang & Bingzong Li

  2. Department of Cell Biology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Ren Ai Road 199, Suzhou, 215123, China

    Qi Su & Wenzhuo Zhuang

  3. Department of Biological Sciences, Xi’an Jiaotong-Liverpool University, Suzhou, China

    Rong Rong

  4. Suzhou Sano Precision Medicine Ltd, Suzhou, China

    Si Chen & Lexin He

  5. Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Xinyun Zhang

Authors
  1. Xinyun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuchen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rong Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Si Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lexin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenzhuo Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bingzong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Wenzhuo Zhuang and Bingzong Li designed the research, Xinyun Zhang and Qi Su performed research, Xinyun Zhang wrote the paper, Rong Rong, Si Chen and Lexin He performed research and modified the paper, Yuchen Zhang analyzed data.

Corresponding authors

Correspondence to Wenzhuo Zhuang or Bingzong Li.

Ethics declarations

Ethical approval

The animal experimentation acquired permission from the ethics committee of Soochow university. The study was conducted in accordance with the Declaration of Helsinki.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 100 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Su, Q., Zhang, Y. et al. A promising natural product in diffuse large B-cell lymphoma therapy by targeting PIM1. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05670-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00277-024-05670-7

Keywords

Search

Navigation