Advanced Search

Journal of Traditional Chinese Medicine >

2024 , Vol. 44 >Issue 1: 78 - 87

DOI: https://doi.org/10.19852/j.cnki.jtcm.20231204.003

Original articles

Efficacy of Yisui granule (益髓颗粒) on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway

  • Jieya WU ,
  • Li HOU ,
  • Xiaoyuan ZHANG ,
  • Gullen Elizabeth ,
  • Chong GAO ,
  • Jing WANG
Expand
  • 1 Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
    2 Department of Pharmacology, Yale Medical School, New Haven, CT 06510, USA
    3 Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China

Received date: 2022-10-17

  Accepted date: 2023-02-21

  Online published: 2023-12-04

Supported by

Clinical Translational Research of Beijing Municipal Science and Technology Commission, Administrative Commission of Zhongguancun Science Park-funded Project: Study on Mechanisms and Efficacy of Yisui granule Treating Low and Intermediate Risk of Myelodysplastic Syndromes via DNA Demethylation(Z211100002921018);National Natural Science Foundation of China-funded Projects: Study on Molecular Mechanisms of Yisui granule Treating Myelodysplastic Syndromes via Regulating DNA Methylation(81503575);Mechanism Study of Tea Polyphenols activating cGAS-STING Pathway to Inhibit Lung Adenocarcinoma Immune Escape based on Redox Balance(82172760);Golden Bridge Project of Beijing Association for Science and Technology-funded Project: Study on Mechanisms of Yisui granule Treating Low and Intermediate Risk of Myelodysplastic Syndromes via DNA Demethylation(ZZ20059)

Fold

Abstract

OBJECTIVE: To unmask the underlying mechanisms of Yisui granule (益髓颗粒, YSG) for the treatment of Myelodysplastic syndromes (MDS).

METHODS: Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety, assess its effect on overall survival (OS), and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5 (sFRP5) gene and suppressing Wnt/β-catenin pathway. Bisulfite amplicon sequencing was applied to detect the level of methylation of the sFRP5 gene; western blotting, immunofluorescence staining, and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1 (DNMT1), sFRP5, and other Wnt/β-catenin pathway-related mRNA and protein expression.

RESULTS: The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine, improved OS, and reduced long-term adverse effects in the long term. Mechanically, YSG reduced the expression of DNMT1 methyltransferase, decreased the methylation, and increased the expression of the Wnt/β-catenin pathway antagonist-sFRP5. Furthermore, components of the Wnt/β-catenin pathway, including Wnt3a, β-catenin, c-Myc, and cyclinD1, were down-regulated in response to YSG, suggesting that YSG could treat MDS by demethylating the sFRP5 gene and suppressing the Wnt/β-catenin pathway.

CONCLUSIONS: Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model, providing an alternative solution for treating MDS.

Key words： myelodysplastic syndromes; Wnt signaling pathway; beta catenin; decitabine; survival; adverse effects; sFRP5 gene methylation; Yisui granule

Cite this article

Jieya WU , Li HOU , Xiaoyuan ZHANG , Gullen Elizabeth , Chong GAO , Jing WANG . Efficacy of Yisui granule (益髓颗粒) on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway[J]. Journal of Traditional Chinese Medicine, 2024 , 44(1) : 78 -87 . DOI: 10.19852/j.cnki.jtcm.20231204.003

References

1. Cabezón M, Malinverni R, Bargay J, et al. Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival. Clin Epigenetics 2021; 13: 1-14.
2. Jones PA, Issa J-PJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet 2016; 17: 630-41.
3. Mohammad HP, Barbash O, Creasy CL. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat Med 2019; 25: 403-18.
4. Zhou JD, Zhang TJ, Xu ZJ, et al. Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes. Cell Death Dis 2020; 11: 1-15.
5. Reilly B, Tanaka TN, Diep D, et al. DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes. Blood Adv 2019; 3: 2845-58.
6. Jiang Y, Liu L, Wang J, Cao Z, Zhao Z. The Wilms' tumor gene-1 is a prognostic factor in myelodysplastic syndrome: a Meta analysis. Oncotarget 2018; 9: 16205-12.
7. Yang K, Wang X, Zhang H, et al. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies. Lab Invest 2016; 96: 116-36.
8. Wang H, Fan R, Wang XQ, et al. Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. Ann Hematol 2013; 92: 199-209.
9. Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409-14.
10. Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003; 423: 448-52.
11. Fenaux P. Myelodysplastic syndromes: from pathogenesis and prognosis to treatment. Semin Hematol 2004; 41: 6-12.
12. Stomper J, Rotondo JC, Greve G, Lubbert M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia 2021; 35: 1873-89.
13. Gil-Perez A, Montalban-Bravo G. Management of myelodysplastic syndromes after failure of response to hypomethylating agents. Ther Adv Hematol 2019; 10: 1-18.
14. Zeidan AM, Hu X, Zhu W, et al. Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents. Leuk Lymphoma 2020; 61: 397-408.
15. Bernal T, Martínez-Camblor P, Sánchez-García J, et al. Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry. Leukemia 2015; 29: 1875-81.
16. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase Ⅲ study. Lancet Oncol 2009; 10: 223-32.
17. Zeidan A, Sekeres M, Garcia-Manero G, et al. Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia 2016; 30: 649-57.
18. Zeidan AM, Stahl M, Sekeres MA, Steensma DP, Komrokji RS, Gore SD. A call for action: increasing enrollment of untreated patients with higher-risk myelodysplastic syndromes in first-line clinical trials. Cancer 2017; 123: 3662-72.
19. Gao C, Wang J, Li Y, et al. Incidence and risk of hematologic toxicities with hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukopenia: a systematic review and Meta-analysis. Medicine 2018; 97:e11860.
20. Boumber Y, Kantarjian H, Jorgensen J, et al. A randomized study of decitabine versus conventional care for maintenance therapy in patients with acute myeloid leukemia in complete remission. Leukemia 2012; 26: 2428-31.
21. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood 2015; 126: 291-9.
22. Lübbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29: 1987-96.
23. Palmieri R, Paterno G, De Bellis E, et al. Therapeutic choice in older patients with acute myeloid leukemia: a matter of fitness. Cancers 2020; 12: 120.
24. Li D. Clinic study of the patients infection rate with myelodysplastic syndromes decreased by Yisui granules. Zhong Guo Yi Yao Xue Bao 1998; 13: 27-30.
25. Hu KW, Sun YL, Le ZS, et al. A clinical study on the treatment of myeloproliferative syndrome by strengthening Qi, nourishing Yin and activating the blood. Beijing Zhong Yi Yao Da Xue Xue Bao 1994; 17: 39-44.
26. Li R, Pan Y, Wu J, et al. Study on Yisui granules in improving anemia and related symptoms in patients with low- and intermediate-risk type I myelodysplastic syndromes. Beijing Zhong Yi Yao 2021; 40: 456-60.
27. Ma J. Clinical observation of Yisui granule treating chemotherapy related-anemia. Shanxi Zhong Yi 2016; 32: 13-5, 20.
28. Chen XY, Wei Y, Su W, et al. Influence of Yisui granules on T-cell subgroups of patients with myelodysplastic syndromes analysed. Zhong Guo Zhong Yi Ji Chu Yi Xue Za Zhi 1995: 32-3.
29. Wu X, Li D, Chen X, et al. Study on the effect of Yisui granule on CD4+CD25+Foxp3+Treg cell and its related cytokines in spleen of ITP mouse. Dang Dai Yi Xue 2010; 16:1-3.
30. Shi X. Modern medical laboratory animal science. Beijing: Beijing People's Military Medical Press, 2000: 239-323.
31. Yang X, Feng Y, Liu Y, et al. Fuzheng Jiedu Xiaoji formulation inhibits hepatocellular carcinoma progression in patients by targeting the AKT/CyclinD1/p21/p27 pathway. Phytomedicine 2021; 87: 153575.
32. Gruenbaum Y, Cedar H, Razin A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 1982; 295: 620-2.
33. Bhagat TD, Chen S, Bartenstein M, et al. Epigenetically aberrant stroma in MDS propagates disease via Wnt/beta-catenin activation. Cancer Res 2017; 77: 4846-57.
34. Cui C, Zhou X, Zhang W, Qu Y, Ke X. Is β-catenin a druggable target for cancer therapy? Trends Biochem Sci 2018; 43: 623-34.
35. Lecarpentier Y, Schussler O, Hébert J-L, Vallée A. Multiple targets of the canonical WNT/β-catenin signaling in cancers. Front Oncol 2019; 9: 1248.
36. Canaani J. Emerging therapies for the myelodysplastic syndromes. Clin Hematol Int 2020; 2:13.
37. Gao X, Wang YY, Li YX, et al. Huganpian, a Traditional Chinese Medicine, inhibits liver cancer growth in vitro and in vivo by inducing autophagy and cell cycle arrest. Biomed Pharmacother 2019; 120: 109469.
38. Kostroma II, Gritsaev SV, Sidorova ZY, et al. Aberrant methylation of promoter regions of sox7, p15ink4b and WNT pathway antagonist genes in patients with myelodysplastic syndrome. Haematologica 2016; 101: 495-6.
39. Gao LS, Meng SP. Comparative study between HL-60 reduced by Yisuiling and single nucleus of umbilical cord blood apoptosis. Zhong Hua Zhong Yi Yao Za Zhi 2000; 15: 26-8.
40. Zhang HJ, Song YH, Sun YL, Chen XY. The effect of Yisui Ling on the proliferation and differentiation of a leukemic megakaryocyte cell line HI-MEG. Zhong Guo Zu Zhi Hua Xue Yu Xi Bao Hua Xue Za Zhi 1996; 5: 483-8.
41. Zhang HJ, Chen XY, Song YH, Hu KW, Sun YL. Preliminary study on effect of YSL on gene expressions of HI-Meg. Zhong Guo Zhong Yi Ji Chu Yi Xue Za Zhi 1996; 2: 43+8.
42. Duffy MJ, O'Grady S, Tang M, Crown J. MYC as a target for cancer treatment. Cancer Treat Rev 2021; 94: 102154.
43. Li S, Deng G, Su J, et al. A novel all-trans retinoic acid derivative regulates cell cycle and differentiation of myelodysplastic syndrome cells by USO1. Eur J Pharmacol 2021: 174199.
44. Huang LJ, Dai D, Shen XH. Exploring the action mechanism of astragalus-codonopsis on myelodysplastic syndrome based on network pharmacology. Zhong Yi Lin Chuang Yan Jiu 2021; 13: 1-6.
45. Gong JM, Zhou YQ, Lin Q. Hydroxysafflor yellow A inhibits ovarian cancer growth through Wnt/β-catenin signaling pathway. Yi Xue Yan Jiu Za Zhi 2019; 48: 131-4.
46. Wang LY, Sun JL, Su JR. Effect of total flavonoids from caulis spatholepis on human breast cancer cell line MCF-7 and its regulation of Wnt/β-catenin pathway. Zhong Yi Xue Bao 2021; 36: 1512-8.
47. Lam W, Ren Y, Guan F, et al. Mechanism based quality control (MBQC) of herbal products: a case study YIV-906 (PHY906). Front Pharmacol 2018; 9: 1324.
Options
Outlines

/

〈 〉