Ouabain reverses imatinib resistance in chronic myeloid leukemia by targeting the Wnt/β‑catenin signaling pathway

Yang Wei; Zhao Tianqi; Shu Qi; Weng Xinhua; Liu Yingxi; Jin Mingrui; Feng Min; Hu Jing

doi:10.13406/j.cnki.cyxb.004091

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Ouabain reverses imatinib resistance in chronic myeloid leukemia by targeting the Wnt/β‑catenin signaling pathway

Basic research | 更新时间：2026-05-13

- Ouabain reverses imatinib resistance in chronic myeloid leukemia by targeting the Wnt/β‑catenin signaling pathway
- Journal of Chongqing Medical University Vol. 51, Issue 5, Pages: 662-668(2026)
- 作者机构：
  
  1.重庆医科大学基础医学院，重庆 400016
  2.重庆医科大学第一临床学院，重庆 400016
  3.重庆医科大学检验医学院/教育部临床检验诊断学重点实验室，重庆 400016
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.004091
  CLC： R733.72
- Received：28 February 2026，
  
  Revised：2026-03-24，
  
  Accepted：30 March 2026，
  
  Published：28 May 2026
- 稿件说明：
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杨薇，赵天祺，舒琦，等.哇巴因靶向Wnt/β-catenin信号通路逆转慢性髓系白血病的伊马替尼耐药[J].重庆医科大学学报，2026，51（5）：662-668.

Yang Wei,Zhao Tianqi,Shu Qi,et al.Ouabain reverses imatinib resistance in chronic myeloid leukemia by targeting the Wnt/β‑catenin signaling pathway[J].Journal of Chongqing Medical University,2026,51(5):662-668.
杨薇，赵天祺，舒琦，等.哇巴因靶向Wnt/β-catenin信号通路逆转慢性髓系白血病的伊马替尼耐药[J].重庆医科大学学报，2026，51（5）：662-668. DOI： 10.13406/j.cnki.cyxb.004091.

Yang Wei,Zhao Tianqi,Shu Qi,et al.Ouabain reverses imatinib resistance in chronic myeloid leukemia by targeting the Wnt/β‑catenin signaling pathway[J].Journal of Chongqing Medical University,2026,51(5):662-668. DOI： 10.13406/j.cnki.cyxb.004091.

摘要

目的

探讨哇巴因靶向Wnt/β-catenin信号通路逆转慢性髓系白血病（chronic myeloid leukemia，CML）伊马替尼（imatinib，IM）耐药的作用及机制。

方法

体外以IM耐药细胞株K562R为研究对象，通过细胞活力检测和集落形成实验观察哇巴因单用或与IM联用的抗白血病效应；通过蛋白免疫印迹法（Western blot）检测K562R细胞中β-catenin、Cyclin D1的蛋白表达水平；体内建立IM耐药CML小鼠模型，通过外周血白细胞计数、血涂片染色、组织病理学技术及生存分析等评价联合治疗方案的体内抗白血病疗效。

结果

体外实验显示，哇巴因与IM具有协同治疗作用，可明显抑制K562R细胞的活力及克隆形成能力（

0.001），并同时下调β-catenin（

0.01）和Cyclin D1（

0.001）的表达水平。体内实验显示，CML小鼠对IM治疗不敏感，与对照组相比，哇巴因联合IM治疗可有效控制CML小鼠的白血病负荷，缓解小鼠体质量减轻（

0.001），降低外周血中白细胞总数（

0.05），减少外周血及骨髓中的白血病细胞浸润，减轻肝（

0.01）、脾（

0.001）的质量，并明显延长CML小鼠的生存期。

结论

哇巴因能够增强CML对IM的敏感性，这可能与抑制Wnt/β-catenin信号通路有关。

Abstract

Objective

To investigate the effect and mechanism of ouabain in reversing imatinib（IM） resistance in chronic myeloid leukemia（CML） by targeting the Wnt/β-catenin signaling pathway.

Methods

In vitro experiments were performed using the IM‑resistant K562R cell line. CCK‑8 assay and colony formation assay were used to detect the anti‑leukemic effects of ouabain alone or in combination with IM. Western blot was applied to measure the protein expression levels of β‑catenin and Cyclin D1 in K562R cells. For

in vivo

study，a IM-resistant CML mouse model was established. The anti‑leukemic efficacy of the combination therapy was evaluated by peripheral white blood cell count，blood smear staining，histopathological techniques，and survival analysis.

Results

In vitro experiments showed that ouabain exerted a synergistic therapeutic effect with IM，significantly inhibiting the viability and clonogenic capacity of K562R cells（

0.001），and downregulating the expression levels of β-catenin（

0.01） and Cyclin D1（

0.001）.

In vivo

experiments demonstrated that CML mice were insensitive to IM treatment，whereas the combination of ouabain and IM effectively controlled the leukemic burden in CML mice，alleviated body weight loss（

0.001），reduced the total peripheral white blood cell count（

0.05），and significantly decreased leukemic cell infiltration in both peripheral blood and bone marrow compared with the control group. Additionally，the weights of the liver（

0.01） and spleen（

0.001） were reduced，and the survival of CML mice was significantly prolonged.

Conclusion

Ouabain enhanced the sensitivity of CML to IM therapy，which may be associated with the inhibition of the Wnt/β-catenin signaling pathway.

关键词

Keywords

references

Jabbour E ， Kantarjian H . Chronic myeloid leukemia：a review [J ] . JAMA ， 2025 ， 333 （ 18 ）： 1618 - 1629 ．

Singh P ， Kumar V ， Gupta SK ， et al . Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs：a review [J ] . Med Oncol ， 2021 ， 38 （ 1 ）： 10 ．

Jabbour E ， Kantarjian H . Chronic myeloid leukemia：2025 update on diagnosis，therapy，and monitoring [J ] . Am J Hematol ， 2024 ， 99 （ 11 ）： 2191 - 2212 ．

Guilhot F ， Hehlmann R . Long-term outcomes of tyrosine kinase inhibitors in chronic myeloid leukemia [J ] . Blood ， 2025 ， 145 （ 9 ）： 910 - 920 .

Soverini S ， Martelli M ， Bavaro L ， et al . Treatment-free remission in chronic myeloid leukemia：the emerging role of novel therapeutic strategies [J ] . Leukemia ， 2024 ， 38 （ 1 ）： 1 - 12 .

Bugter JM ， Fenderico N ， Maurice MM . Mutations and mechanisms of WNT pathway tumour suppressors in cancer [J ] . Nat Rev Cancer ， 2021 ， 21 （ 1 ）： 5 - 21 ．

Ng JJ ， Ong ST . Therapy resistance and disease progression in CML：mechanistic links and therapeutic strategies [J ] . Curr Hematol Malig Rep ， 2022 ， 17 （ 6 ）： 181 - 197 ．

Kozik M ， Giotopoulos G ， Huntly BJP . Leukemic stem cells：from leukemic niche to therapeutic opportunities [J ] . Blood Rev ， 2023 ， 57 ： 100997 .

Shi X ， Liu Y ， Zhang J ， et al . Wnt/β-catenin signaling in leukemia：a new therapeutic target [J ] . Front Oncol ， 2023 ， 13 ： 1123456 .

Toth RK ， Warfel NA . Targeting PIM kinases to overcome therapeutic resistance in cancer [J ] . Mol Cancer Ther ， 2021 ， 20 （ 1 ）： 3 - 10 ．

Zhou YY ， Jian SQ ， Lu LJ ， et al . Targeting the N-cadherin/β-catenin axis with MSAB reverses malignant phenotypes in blast crisis of CML [J ] . Front Oncol ， 2025 ， 15 ： 1657508 ．

Weidemann H ， Sarsour AD ， Brodie C . Ouabain-a double-edged sword in tumor development and progression? a review of half a century [J ] . Front Physiol ， 2025 ， 16 ： 1685871 ．

Dhalla NS ， Elimban V ， Adameova AD . Role of Na + -K + ATPase alterations in the development of heart failure [J ] . Int J Mol Sci ， 2024 ， 25 （ 19 ）： 10807 ．

Bejček J ， Spiwok V ， Kmoníčková E ， et al . Na + /K + -ATPase revisited：on its mechanism of action，role in cancer，and activity modulation [J ] . Molecules ， 2021 ， 26 （ 7 ）： 1905 ．

Sun C ， Liu J ， Zhai SQ ， et al . Inhibitory effect of ouabain on resistance to imatinib in chronic myeloid leukemia K562/G01 cells [J ] . Indian J Pharm Sci ， 2023 ， 85 （ 3 ）： 621 - 631 ．

Ren YL ， Anderson AT ， Meyer G ， et al . Digoxin and its Na + /K + -ATPase-targeted actions on cardiovascular diseases and cancer [J ] . Bioorg Med Chem ， 2024 ， 114 ： 117939 ．

Liu JQ ， Xiao Q ， Xiao JN ， et al . Wnt/β-catenin signalling：function，biological mechanisms，and therapeutic opportunities [J ] . Signal Transduct Target Ther ， 2022 ， 7 （ 1 ）： 3 ．

Mojtahedi H ， Yazdanpanah N ， Rezaei N . Chronic myeloid leukemia stem cells：targeting therapeutic implications [J ] . Stem Cell Res Ther ， 2021 ， 12 （ 1 ）： 603 ．

Láinez-González D ， Alonso-Aguado AB ， Alonso-Dominguez JM . Understanding the Wnt signaling pathway in acute myeloid leukemia stem cells：a feasible key against relapses [J ] . Biology ， 2023 ， 12 （ 5 ）： 683 .

Liu Y ， Chen X ， Zhang L ， et al . Cardiac glycosides as novel anti-cancer agents：Mechanisms and clinical perspectives [J ] . Signal Transduct Target Ther ， 2023 ， 8 （ 1 ）： 215 .

Amarante-Mendes GP ， Rana A ， Santos Datoguia T ， et al . BCR-ABL1 tyrosine kinase complex signaling transduction：challenges to overcome resistance in chronic myeloid leukemia [J ] . Pharmaceutics ， 2022 ， 14 （ 1 ）： 215 ．

Fujii T ， Shimizu T ， Sakai H . Pathophysiological roles of two intracellular P-type ATPases：the cancer-associated Na + ，K + -ATPase α3 isoform and the Parkinson’s disease-related ATP13A2 [J ] . Int J Mol Sci ， 2026 ， 27 （ 4 ）： 1800 ．

Poohadsuan J ， O’Doherty GA ， Owattanapanich W ， et al . Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status [J ] . Cell Commun Signal ， 2023 ， 21 （ 1 ）： 283 ．

Bansal M ， Verma M . Potential therapeutic targets in chronic myeloid leukemia [J ] . Med Oncol ， 2025 ， 42 （ 8 ）： 344 ．

Xiao SY ， Tong MQ ， Ren JY ， et al . Cardiac glycosides toxicity：Mechanisms and mitigation strategies in recent studies [J ] . Chem Biol Interact ， 2026 ， 423 ： 111817 ．

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