Antagonistic interaction of HSP90 inhibitor XL-888 and 5-FU combination treatment in breast cancer cells

Year 2024, Volume: 8 Issue: 2, 84 - 90, 20.08.2024

Nazan Gökşen Tosun

https://doi.org/10.35860/iarej.1348930

Abstract

Breast cancer is a serious global health problem, and investigation of innovative therapeutic approaches in its treatment is important to increase survival. Combination therapy targets more than one mechanism simultaneously and has recently emerged as an effective treatment strategy by using different therapeutic agents together. The purpose of this study was to determine the combined effects of the conventional chemotherapeutic agent 5-Fluorouracil (5-FU) and the HSP90 inhibitor XL-888 on breast cancer cell lines. MDA-MB-231 and MCF-7 cells were subjected to varying concentrations of XL-888 and 5-FU as individual treatments and in combination. The MTT test was employed to determine cell viability, and the Chou-Talalay technique was utilized to compute combination indices. Contrary to expectations, the HSP90 inhibitor XL-888 and 5-FU coadministration showed antagonistic effects in MDA-MB-231 and MCF-7 breast cancer cells. The results highlight the importance of careful consideration when combining these agents in breast cancer treatment regimens because their co-administration may not produce the expected synergistic results. The implications of the present research are anticipated to contribute to the developing of enhanced and focused treatment modalities for various cancers, with a particular emphasis on breast cancer.

Keywords

Antagonistic effect, Combination therapy, XL-888, 5-fluorouracil

Thanks

The author would like to thank Prof. Dr. İsa GÖKÇE and Dr. Özlem KAPLAN for contributions.

References

• 1. Wu, J., T. Liu, Z. Rios, Q. Mei, X. Lin, and S. Cao, Heat Shock Proteins and Cancer. Trends in Pharmacological Sciences, 2017. 38(3): p. 226–256.
• 2. Keklikcioğlu Çakmak, N., M. Küçükyazıcı, and A. Eroğlu, Synthesis and stability analysis of folic acid-graphene oxide nanoparticles for drug delivery and targeted cancer therapies. International Advanced Researches and Engineering Journal, 2019. 3(2): p. 81–85.
• 3. Lakkakula, J.R., R.W.M. Krause, D. Divakaran, S. Barage, and R. Srivastava, 5-Fu inclusion complex capped gold nanoparticles for breast cancer therapy. Journal of Molecular Liquids, 2021. 341: p. 117262.
• 4. Wang, F., H. Zhang, H. Wang, T. Qiu, B. He, and Q. Yang, Combination of AURKA inhibitor and HSP90 inhibitor to treat breast cancer with AURKA overexpression and TP53 mutations. Medical Oncology, 2022. 39(12): p. 180.
• 5. Bussenius, J., C.M. Blazey, N. Aay, N.K. Anand, A. Arcalas, T. Baik, K.D. Rice, Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90. Bioorganic & Medicinal Chemistry Letters, 2012. 22(17): p. 5396–5404.
• 6. Akce, M., O.B. Alese, W.L. Shaib, C. Wu, G.B. Lesinski, B.F. El-Rayes, Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies: Results of the dose-escalation phase. Journal of Clinical Oncology, 2020. 38(4): p. 830.
• 7. Li, Z.N., Y. Luo, HSP90 inhibitors and cancer: Prospects for use in targeted therapies. Oncology Reports, 2023. 49(1).
• 8. Jhaveri, K., T. Taldone, S. Modi, and G. Chiosis, Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2012. 1823(3): p. 742–755.
• 9. Huryn, D.M., and P. Wipf, Chapter 3 - Natural Product Chemistry and Cancer Drug Discovery. In S. B. T.-C. D. D. and D. (Second Edition), Neidle (Ed.), 2014. p. 91–120.
• 10. Lyman, S.K., S.C. Crawley, R. Gong, J. I. Adamkewicz, G. McGrath, J.Y. Chew, R.A. Blake, High-Content, High-Throughput Analysis of Cell Cycle Perturbations Induced by the HSP90 Inhibitor XL888. PLOS ONE, 2011. 6(3): p. e17692.
• 11. Jaaks, P., E.A. Coker, D.J. Vis, O. Edwards, E.F. Carpenter, S.M. Leto, M.J. Garnett, Effective drug combinations in breast, colon and pancreatic cancer cells. Nature, 2022. 603(7899): p. 166–173.
• 12. Pegram, M., C. Jackisch, S.R.D. Johnston, Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer. Breast Cancer, 2023. 9(1): p. 45.
• 13. Erden Tayhan, S., A study with cancer stem cells and three-dimensional tumoroids: investigation of the combined effects of 5-fluorouracil and doxorubicin in breast cancer. Medical Oncology, 2024. 41(7): p. 185.
• 14. Keith, C.T., A.A. Borisy, and B.R. Stockwell, Multicomponent therapeutics for networked systems. Nature Reviews Drug Discovery, 2005. 4(1): p. 71–78.
• 15. Chou, T. C., The mass-action law-based algorithms for quantitative econo-green bio-research. Integrative Biology: Quantitative Biosciences from Nano to Macro, 2011. 3(5): p. 548–559.
• 16. Zhang, N., J.N. Fu, and T.C. Chou, Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method. American Journal of Cancer Research, 2016. 6(1): p. 97–104.
• 17. Banerjee, V., N. Sharda, J. Huse, D. Singh, D. Sokolov, S.J. Czinn, A. Banerjee, Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method. European Journal of Pharmacology, 2021. 897: p. 173919.
• 18. Kamal, A., L. Thao, J. Sensintaffar, L. Zhang, M.F. Boehm, L.C. Fritz, F.J. Burrows, A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors. Nature, 2003. 425(6956): p. 407–410.
• 19. Friedland, J.C., D.L. Smith, J. Sang, J. Acquaviva, S. He, C. Zhang, D.A. Proia, Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes. Investigational New Drugs, 2014. 32(1): p. 14–24.
• 20. Gorska, M., A. Marino Gammazza, M.A. Zmijewski, C. Campanella, F. Cappello, T. Wasiewicz, M. Wozniak, Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60). PLOS ONE, 2013. 8(8): p. e71135.
• 21. Modi, S., A. Stopeck, H. Linden, D. Solit, S. Chandarlapaty, N. Rosen, C. Hudis, HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab. Clinical Cancer Research, 2011. 17(15): p. 5132–5139.
• 22. Pick, E., Y. Kluger, J.M. Giltnane, C. Moeder, R.L. Camp, D.L. Rimm, H.M. Kluger, High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer. Cancer Research, 2007. 67(7): p. 2932–2937.
• 23. Özgür, A., A. Kara, N. Gökşen Tosun, Ş. Tekin, İ. Gökçe, Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines. Molecular Biology Reports, 2021. 48(4): p. 3439–3449.
• 24. Proia, D.A., C. Zhang, M. Sequeira, J.P. Jimenez, S. He, N. Spector, I. El-Hariry, Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer. Clinical Cancer Research, 2014. 20(2): p. 413–424.
• 25. Mohammadian, M., S. Feizollahzadeh, R. Mahmoudi, A. Toofani Milani, S. Rezapour-Firouzi, B. Karimi Douna, Hsp90 Inhibitor; NVP-AUY922 in Combination with Doxorubicin Induces Apoptosis and Downregulates VEGF in MCF-7 Breast Cancer Cell Line. Asian Pacific Journal of Cancer Prevention: APJCP, 2020. 21(6): p. 1773–1778.
• 26. Sarder, A., M.G. Rabbani, A. S.M.H.K. Chowdhury, M. E. Sobhani, Molecular Basis of Drug Interactions of Methotrexate, Cyclophosphamide and 5-Fluorouracil as Chemotherapeutic Agents in Cancer. Biomedical Research and Therapy, 2015. 2(2): p. 5.
• 27. Park, J.H., S.A. Im, J.M. Byun, K.H. Kim, J.S. Kim, I.S. Choi, T.Y. Kim, Cyclophosphamide, Methotrexate, and 5-Fluorouracil as Palliative Treatment for Heavily Pretreated Patients with Metastatic Breast Cancer: A Multicenter Retrospective Analysis. Journal of Breast Cancer, 2017. 20(4): p. 347–355.
• 28. Sethy, C., and C.N. Kundu, 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomedicine & Pharmacotherapy, 2021. 137: p. 111285.
• 29. Chou, T.C., Frequently asked questions in drug combinations and the mass-action law-based answers. Synergy, 2014. 1(1): p. 3–21.
• 30. Chou, T.C., The combination index (CI < 1) as the definition of synergism and of synergy claims. Synergy, 2018. 7: p. 49–50.
• 31. Feng, Q., C. Zhang, D. Lum, J.E. Druso, B. Blank, K.F. Wilson, R.A. Cerione, A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis. Nature Communications, 2017. 8(1): p. 14450.
• 32. Sveen, A., J. Bruun, P.W. Eide, I.A. Eilertsen, L. Ramirez, A. Murumägi, R.A. Lothe, Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 2018. 24(4): p. 794–806.
• 33. Liu, Y., X. Wang, Y. Wang, Y. Zhang, K. Zheng, H. Yan, Y. Wang, Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells. International Journal of Oncology, 2015. 46(1): p. 299–307.
• 34. Kaplan, Ö., Synergistic induction of apoptosis in liver cancer cells: exploring the combined potential of doxorubicin and XL-888. Medical Oncology (Northwood, London, England), 2023. 40(11): p. 318.
• 35. Gökşen Tosun, N., Enhancing therapeutic efficacy in breast cancer: a study on the combined cytotoxic effects of doxorubicin and MPC-3100. Naunyn-Schmiedeberg’s Archives of Pharmacology, 2023.
• 36. Kaplan, Ö., Evaluation of combined use of hsp90 inhibitor mpc-3100 and traditional cancer drug 5-fu on liver cancer cell lines. Journal of Scientific Reports-A, 2023. 055: p. 60–69.
• 37. Daunys, S., D. Matulis, V. Petrikaitė, Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures. Scientific Reports, 2019. 9(1): p. 16177.
• 38. Kaplan, Ö., N. Gökşen Tosun, Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line. Medical Oncology, 2024. 41(8): p. 194.
• 39. Park, M., E. Jung, J.M. Park, S. Park, D. Ko, J. Seo, J.H. Seo, The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer. Theranostics, 2024. 14(6): p. 2442–2463.