Vol. 3 No. 1 (2026)

Research Articles

Evaluation of the inhibitory effect of 2,5-Dimethyl-Celecoxib on tamoxifen-sensitive and -resistant human breast cancer cells (MCF-7)

Published 2026-01-31

  • Yingfen Wang
    • ,
  • Chao Li
    • ,
  • Aoying Li
    • ,
  • Peijun Liu
    • ,
  • Xuemei Yan
    • ,
  • Tan Tan

Yingfen Wang
University of South China image/svg+xml

Chao Li
Department of Oncology and Hematology, The Fourth People's Hospital of Chenzhou , Chenzhou 423000, China

Aoying Li
University of South China image/svg+xml

Peijun Liu
First Affiliated Hospital of Xi'an Jiaotong University image/svg+xml

Xuemei Yan
University of South China image/svg+xml

Tan Tan
University of South China image/svg+xml

Abstract

Acquired endocrine-resistance has become a big clinical challenge in breast cancer endocrine therapy.We previously reported that simvastatin inhibited TamR cell growth by reducing the expression of minichromosome maintenance protein 7 (MCM7) and retinoblastoma protein (Rb), which caused a significant up-regulation of γH2AX expression and subsequently induces DNA damage.Our previous studies have demonstrated that 2,5-dimethyl-celecoxib (DMC) can significantly reduce MCM7 and Rb protein expression in both MCF-7 and MCF-7/TamR cell lines. Aimed to investigate the effect of DMC on the proliferation of TAM-sensitive and -resistant breast cancer cell lines as well as to evaluate the possible underlying inhibitory mechanism, MTT and apoptosis analysis were performed to detect cell proliferation and apoptosis.Western blotting assays were performed to analyse the protein expression levels of cell cycle and apoptosis regulators. Furthermore, immunofluorescence and comet assays were carried out to explore the mechanism of DNA damage.Finally, in vivo experiments are performed to verify the results of in vitro experiments. The results demonstrated that DMC inhibited the proliferation and increased the apoptosis of both TAM-sensitive and -resistant breast cancer cells in vitro. In addition, DMC was observed to down-regulate Rb/MCM7 and induce DNA damage, particularly when used in combination with TAM. Notably,DMC also proved to have the same effect in vivo model. In summary , the growth inhibition generated by DMC may be achieved by inhibiting the protein expression of Rb/MCM7 and subsequently inducing DNA damage. This study provides a novel strategy for the treatment of TamR breast cancer patients in the clinical setting.

Keywords

Tamoxifen resistance, DMC, DNA damage, MCM7

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References

  1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. DOI: https://doi.org/10.3322/caac.21834
  2. O'Shaughnessy J, Tolaney SM, Yardley DA, et al. Real-world risk of recurrence and treatment outcomes with adjuvant endocrine therapy in patients with stage II-III HR+/HER2- early breast cancer. Breast. 2025;81:104437. DOI: https://doi.org/10.1016/j.breast.2025.104437
  3. Xiong X, Zheng LW, Ding Y, et al. Breast cancer: pathogenesis and treatments. Signal Transduct Target Ther. 2025;10(1):49. DOI: https://doi.org/10.1038/s41392-024-02108-4
  4. Javankiani S, Bolandi S, Soleimani A, et al. MAPK signaling mediates tamoxifen resistance in estrogen receptor-positive breast cancer. Mol Cell Biochem. 2025;480(9):4973-4989.
  5. Das GM, Oturkar CC, Menon V. Interaction between Estrogen Receptors and p53: A Broader Role for Tamoxifen?. Endocrinology. 2025;166(3):bqaf020. DOI: https://doi.org/10.1210/endocr/bqaf020
  6. Javankiani S, Bolandi S, Soleimani A, et al. MAPK signaling mediates tamoxifen resistance in estrogen receptor-positive breast cancer. Mol Cell Biochem. 2025;480(9):4973-4989. DOI: https://doi.org/10.1007/s11010-025-05304-0
  7. S. Mallick, R. Benson, P.K. Julka, Breast cancer prevention with anti-estrogens: review of the current evidence and future directions, Breast cancer (Tokyo, Japan) 23 (2016) 170-177. DOI: https://doi.org/10.1007/s12282-015-0647-2
  8. S. Nikanfar, S. Atari-Hajipirloo, F. Kheradmand, J. Rashedi, A. Heydari, Cytotoxic effect of 2, 5-dimethyl-celecoxib as a structural analog of celecoxib on human colorectal cancer (HT-29) cell line, Cellular and molecular biology (Noisy-le-Grand, France) 64 (2018) 8-13. DOI: https://doi.org/10.14715/cmb/2018.64.7.2
  9. Rybarczyk A, Majchrzak-Celińska A, Piwowarczyk L, Krajka-Kuźniak V. The Anti-Glioblastoma Effects of Novel Liposomal Formulations Loaded with Cannabidiol, Celecoxib, and 2,5-Dimethylcelecoxib. Pharmaceutics. 2025;17(8):1031. DOI: https://doi.org/10.3390/pharmaceutics17081031
  10. S. Atari-Hajipirloo, S. Nikanfar, A. Heydari, F. Kheradmand, Imatinib and its combination with 2,5-dimethyl-celecoxibinduces apoptosis of human HT-29 colorectal cancer cells, Research in pharmaceutical sciences 12 (2017) 67-73. DOI: https://doi.org/10.4103/1735-5362.199049
  11. S.J. Kim, G.H. Ha, J.H. Bae, G.R. Kim, C.H. Son, Y.S. Park, K. Yang, S.O. Oh, S.H. Kim, C.D. Kang, COX-2- and endoplasmic reticulum stress-independent induction of ULBP-1 and enhancement of sensitivity to NK cell-mediated cytotoxicity by celecoxib in colon cancer cells, Experimental cell research 330 (2015) 451-459. DOI: https://doi.org/10.1016/j.yexcr.2014.09.008
  12. B. Zhang, Y. Yan, Y. Li, D. Zhang, J. Zeng, L. Wang, M. Wang, N. Lin, Dimethyl celecoxib sensitizes gastric cancer cells to ABT-737 via AIF nuclear translocation, Journal of cellular and molecular medicine 20 (2016) 2148-2159. DOI: https://doi.org/10.1111/jcmm.12913
  13. L.M. Backhus, N.A. Petasis, J. Uddin, A.H. Sch?nthal, R.D. Bart, Y. Lin, V.A. Starnes, R.M. Bremner, Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer, The Journal of thoracic and cardiovascular surgery 130 (2005) 1406-1412. DOI: https://doi.org/10.1016/j.jtcvs.2005.07.018
  14. Gao D, Nyalali AMK, Hou Y, et al. 2,5-Dimethyl Celecoxib Inhibits Proliferation and Cell Cycle and Induces Apoptosis in Glioblastoma by Suppressing CIP2A/PP2A/Akt Signaling Axis. J Mol Neurosci. 2021;71(8):1703-1713. DOI: https://doi.org/10.1007/s12031-020-01773-8
  15. I.A.M. van Roosmalen, C.R. Reis, R. Setroikromo, S. Yuvaraj, J.V. Joseph, P.G. Tepper, F.A.E. Kruyt, W.J. Quax, The ER stress inducer DMC enhances TRAIL-induced apoptosis in glioblastoma, SpringerPlus 3 (2014) 495. DOI: https://doi.org/10.1186/2193-1801-3-738
  16. A. Kardosh, E.B. Golden, P. Pyrko, J. Uddin, F.M. Hofman, T.C. Chen, S.G. Louie, N.A. Petasis, A.H. Schonthal, Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib, Cancer research 68 (2008) 843-851. DOI: https://doi.org/10.1158/0008-5472.CAN-07-5555
  17. A. Kardosh, N. Soriano, Y.T. Liu, J. Uddin, N.A. Petasis, F.M. Hofman, T.C. Chen, A.H. Sch?nthal, Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib, Blood 106 (2005) 4330-4338. DOI: https://doi.org/10.1182/blood-2005-07-2819
  18. A. Kardosh, W. Wang, J. Uddin, N.A. Petasis, F.M. Hofman, T.C. Chen, A.H. Schonthal, Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt's lymphoma in vitro and in vivo, Cancer Biol Ther 4 (2005) 571-582. DOI: https://doi.org/10.4161/cbt.4.5.1699
  19. S. Thomas, N. Sharma, E.B. Golden, H. Cho, P. Agarwal, K.J. Gaffney, N.A. Petasis, T.C. Chen, F.M. Hofman, S.G. Louie, A.H. Schonthal, Preferential killing of triple-negative breast cancer cells in vitro and in vivo when pharmacological aggravators of endoplasmic reticulum stress are combined with autophagy inhibitors, Cancer Lett 325 (2012) 63-71. DOI: https://doi.org/10.1016/j.canlet.2012.05.030
  20. Z. Liang, W. Li, J. Liu, J. Li, F. He, Y. Jiang, L. Yang, P. Li, B. Wang, Y. Wang, Y. Ren, J. Yang, Z. Luo, C. Vaziri, P. Liu, Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells, Scientific reports 7 (2017) 41776. DOI: https://doi.org/10.1038/srep41776
  21. F. Al-Rashed, D. Calay, M. Lang, C.C. Thornton, A. Bauer, A. Kiprianos, D.O. Haskard, A. Seneviratne, J.J. Boyle, A.H. Schonthal, C.P. Wheeler-Jones, J.C. Mason, Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling, Sci Rep 8 (2018) 6271. DOI: https://doi.org/10.1038/s41598-018-24548-z
  22. J. Li, J. Liu, Z. Liang, F. He, L. Yang, P. Li, Y. Jiang, B. Wang, C. Zhou, Y. Wang, Y. Ren, J. Yang, J. Zhang, Z. Luo, C. Vaziri, P. Liu, Simvastatin and Atorvastatin inhibit DNA replication licensing factor MCM7 and effectively suppress RB-deficient tumors growth, Cell death & disease 8 (2017) e2673. DOI: https://doi.org/10.1038/cddis.2017.46
  23. Sakurai K, Chubachi S, Miyata J, et al. Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice. Front Immunol. 2025;16:1557790. DOI: https://doi.org/10.3389/fimmu.2025.1557790
  24. N.L. Barnes, F. Warnberg, G. Farnie, D. White, W. Jiang, E. Anderson, N.J. Bundred, Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer, Br J Cancer 96 (2007) 575-582. DOI: https://doi.org/10.1038/sj.bjc.6603593
  25. V. Jendrossek, Targeting apoptosis pathways by Celecoxib in cancer, Cancer Lett 332 (2013) 313-324. DOI: https://doi.org/10.1016/j.canlet.2011.01.012
  26. F. Kalalinia, F. Elahian, F. Mosaffa, J. Behravan, Celecoxib Up Regulates the Expression of Drug Efflux Transporter ABCG2 in Breast Cancer Cell Lines, Iran J Pharm Res 13 (2014) 1393-1401.
  27. J. Chen, P. Shen, X.C. Zhang, M.D. Zhao, X.G. Zhang, L. Yang, Efficacy and safety profile of celecoxib for treating advanced cancers: a meta-analysis of 11 randomized clinical trials, Clin Ther 36 (2014) 1253-1263. DOI: https://doi.org/10.1016/j.clinthera.2014.06.015
  28. P. Pyrko, N. Soriano, A. Kardosh, Y.T. Liu, J. Uddin, N.A. Petasis, F.M. Hofman, C.S. Chen, T.C. Chen, A.H. Schonthal, Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo, Mol Cancer 5 (2006) 19. DOI: https://doi.org/10.1186/1476-4598-5-19
  29. J.J. Virrey, Z. Liu, H.Y. Cho, A. Kardosh, E.B. Golden, S.G. Louie, K.J. Gaffney, N.A. Petasis, A.H. Schonthal, T.C. Chen, F.M. Hofman, Antiangiogenic activities of 2,5-dimethyl-celecoxib on the tumor vasculature, Molecular cancer therapeutics 9 (2010) 631-641. DOI: https://doi.org/10.1158/1535-7163.MCT-09-0652
  30. H.Y. Cho, S. Thomas, E.B. Golden, K.J. Gaffney, F.M. Hofman, T.C. Chen, S.G. Louie, N.A. Petasis, A.H. Schonthal, Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress, Cancer letters 282 (2009) 87-97. DOI: https://doi.org/10.1016/j.canlet.2009.03.007