Abstract
Amaç: Karmaşık ve çok yönlü bir hastalık grubu olan kanser, küresel sağlık açısından zorlu bir sorun teşkil etmektedir. Kontrolsüz hücre büyümesi ve çoğalması ile karakterize edilen bu hastalık, her biri benzersiz biyolojik özelliklere sahip olan çeşitli formlarda kendini göstermektedir. Kanser biyolojisinin karmaşıklığının anlaşılması, hedefe yönelik terapötik müdahalelerin geliştirilmesi için önemlidir. Bu araştırma, Aurora B kinazın BI 831266 ile inhibe edilmesinin, MCF7 hücrelerinde sisplatinin anti-tümör etkinliği üzerindeki etkisini araştırmayı ve potansiyel tedavi stratejilerini anlamamıza katkıda bulunmayı amaçlamaktadır.
Gereç ve Yöntem: BI 831266 ve sisplatin kombinasyonunun terapötik potansiyelini değerlendirmek amacıyla MCF7 insan meme kanseri hücrelerinin kullanıldığı bu araştırmada İyi Hücre Kültürü Uygulamaları gerçekleştirilmiştir. Fonksiyonel deneylerle ilgili olarak, in vitro hücre proliferasyon analizi, 2D klonojenik sağkalım analizi, 3D koloni formasyon analizi ve yara iyileşme analizi uygulandı. Gözlemlenen fonksiyonel sonuçların altında yatan moleküler mekanizmayı açıklamak için ayrıca SDS-PAGE ve Western blot deneyleri gerçekleştirildi.
Bulgular: Bulgularımız, MCF7 kanser hücrelerinde Aurora B kinazın inhibe edilmesi ile sisplatin tedavisi arasında sinerjistik bir etkileşimi ortaya çıkardı. Kombinasyon tedavisinin, önemli protein ifadelerindeki değişikliklerden de anlaşılacağı üzere sisplatinin sitotoksisitesini önemli ölçüde arttırdığı, kanser hücresi göçünü engellediği ve apoptotik yolakları etkinleştirdiği belirlendi.
Sonuç: Araştırmamız, MCF7 meme kanseri hücrelerinde sisplatinin terapötik yanıtını arttırmak için Aurora B kinaz aktivitesini hedeflemenin önemini vurgulamaktadır. Çalışmamız, meme kanseri tedavisinde daha etkili ve hedefe yönelik bir yaklaşım sunarak potansiyel kombinasyon tedavilerine değerli katkılar sağlamaktadır.
Supporting Institution
Projemiz Bingöl Üniversitesi Bilimsel Araştırma Projeleri (BAP) Birimi tarafından desteklenmiştir.
Project Number
The Scientific Research Projects Coordination Unit of Bingol University, BAP-SHMYO.2023.001
References
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- Smolarz B, Zadrożna Nowak A, Romanowicz H. Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature). Cancers (Basel). 2022;14(10):1–27.
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020 : GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 2021;71(3):209–49.
- Dasari S, Bernard Tchounwou P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364–78.
- Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem [Internet]. 2019;88(March):102925. Available from: https://doi.org/10.1016/j.bioorg.2019.102925
- Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol 2010;28(7):1145–53.
- Sre M, Ml W, Sj E, Beith J, Rf D, Goodwin A, et al. Platinum-based chemotherapy for early triple-negative breast cancer. Cochrane Database Syst Rev 2023;(9):1–147.
- Weimer AK, Demidov D, Lermontova I, Beeckman T, Van Damme D. Aurora kinases throughout plant development. Trends Plant Sci 2016;21(1):69–79.
- Vader G, Lens SMA. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta (BBA)Reviews Cancer. 2008;1786(1):60–72.
- Fu J, Bian M, Jiang Q, Zhang C. Roles of aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007;5(1):1–10.
- Portella G, Passaro C, Chieffi P. Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer. Curr Med Chem 2011;18(4):482–96.
- Richie CT, Golden A. Chromosome Segregation : Aurora B Gets Tousled. 2022;15(10):1–8.
- Libertini S, Abagnale A, Passaro C, Botta G, Portella G. Aurora A and B Kinases - Targets of Novel Anticancer Drugs. Recent Pat Anticancer Drug Discov 2010;5(3):219–41.
- Bavetsias V, Linardopoulos S. Aurora kinase inhibitors: Current status and outlook. Front Oncol 2015;5(DEC):1–2.
- Ma HT, Poon RYC. Aurora kinases and DNA damage response. Mutat Res Fund Mol Mech Mutagen 2020;821.
- Borah NA, Reddy MM. Aurora kinase B inhibition: A potential therapeutic strategy for cancer. Molecules. 2021;26(7):1–30.
- Gundogdu R, Erdogan MK, Sever A, Toy Y. Synergistic effect of RAD50 downregulation on combination of rucaparib and doxorubicin. Ege J Med 2023;62(2):289–300.
- Franken NAPP, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc [Internet]. 2006 Dec 21 [cited 2018 Dec 5];1(5):2315–9. Available from: http://www.nature.com/doifinder/10.1038/nprot.2006.339
- 19. Bettoun A, Joffre C, Zago G, Surdez D, Vallerand D, Gundogdu R, et al. Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation. Oncotarget. 2016;7(28):44142–60.
- Kadir Erdogan M, Halil Gecibesler I, Yapar Y, Gundogdu R, Kirici M, Behcet L, et al. Fatty acid composition, enzyme inhibitory effect, antioxidant and anticancer activity of extract from Saponaria prostrata WILLD. subsp. anatolica HEDGE. Bioorg Chem [Internet]. 2021;113(March):105032. Available from: https://doi.org/10.1016/j.bioorg.2021.105032
- 21. Lee A V, Oesterreich S, Davidson NE. MCF-7 Cells - Changing the Course of Breast Cancer Research and Care for 45 Years. J Natl Cancer Inst 2015;107(7):1–4.
- 22. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 2006;
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- 24. Chaudhry P, Singh M, Parent S, Asselin E. Prostate Apoptosis Response 4 (Par-4), a Novel Substrate of Caspase-3 during Apoptosis Activation. Mol Cell Biol 2012;32(4):826–39.
- 25. Jiang Y, Ji F, Liu Y, He M, Zhang Z, Yang J, et al. Cisplatin-induced autophagy protects breast cancer cells from apoptosis by regulating yes-associated protein. Oncol Rep 2017;38(6):3668–76.
- 26. Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis. Cancer Res 1993;53(17):3976–85.
- 27. McNamee LM, Brodsky MH. P53-independent apoptosis limits DNA damage-induced aneuploidy. Genetics. 2009;182(2):423–35.
- 28. Marchini S, Ciro’ M, Broggini M. p53-Independent caspase-mediated apoptosis in human leukaemic cells is induced by a DNA minor groove binder with antineoplastic activity. Apoptosis. 1999;4(1):39–45.
- 29. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science (80- ). 1998;281(5381):1322–6.
- 30. Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death Differ [Internet]. 2018;25(1):65–80. Available from: http://dx.doi.org/10.1038/cdd.2017.186
- 31. Kaloni D, Diepstraten ST, Strasser A, Kelly GL. BCL-2 protein family: Attractive targets for cancer therapy. Apoptosis. 2023;28(1–2):20–38.
- 32. Kaufmann T, Strasser A, Jost PJ. Fas death receptor signalling: Roles of Bid and XIAP. Cell Death Differ 2012;19(1):42–50.
- 33. Huang D, Huang Y, Huang Z, Weng J, Zhang S, Gu W. Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated aurora B kinase in breast cancer cell lines. Cancer Cell Int [Internet]. 2019;19(1):1–13. Available from: https://doi.org/10.1186/s12935-019-0885-z
- 34. Zeng WF, Navaratne K, Prayson RA, Weil RJ. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 2007;60(2):218–21.
- 35. Nie M, Wang Y, Yu Z, Li X, Deng Y, Wang Y, et al. AURKB promotes gastric cancer progression via activation of CCND1 expression. Aging (Albany NY). 2020;12(2):1304–21.
- 36. Qi G, Ogawa I, Kudo Y, Miyauchi M, Siriwardena BSMS, Shimamoto F, et al. Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 2007;450(3):297–302.
- 37. Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, et al. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 2006;66(3):326 33.
- 38. International BI. Aurora B inhibitor [Internet]. 2024 [cited 2024 Jan 1]. Available from: https://www.opnme.com/molecules/aurb-bi831266
- 39. Larsen SL, Yde CW, Laenkholm AV, Rasmussen BB, Duun-Henriksen AK, Bak M, et al. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer. BMC Cancer. 2015;15(1):1–15.
Abstract
Aim: Cancer, a complex and multifaceted group of diseases, poses a formidable challenge to global health. Characterised by uncontrolled cell growth and proliferation, it manifests in diverse forms, each with unique biological traits. Understanding the complexity of cancer biology is essential for developing targeted therapeutic interventions. This research aimed to explore the impact of inhibiting Aurora B kinase with BI 831266 on the anticancer efficacy of cisplatin in MCF7 cells, contributing to our understanding of potential treatment strategies.
Materials and Methods: Good Cell Culture Practices were conducted in this research, where MCF7 human breast cancer cells were used in order to assess the therapeutic potential of the BI 831266 and cisplatin combination. Regarding functional experiments, we employed in vitro cell proliferation assay, 2D clonogenic survival assay, 3D colony formation assay and wound-healing assay. To elucidate the molecular mechanism underlying the observed functional outcomes, SDS-PAGE and Western blotting experiments were additionally conducted.
Results: Our findings uncovered a synergistic interaction between inhibiting Aurora B kinase and treating MCF7 cancer cells with cisplatin. The combined treatment significantly increased cisplatin's cytotoxicity, hindered cancer cell migration, and influenced apoptotic pathways, as evident from changes in key protein expressions.
Conclusion: Our research emphasises the significance of targeting Aurora B kinase in order to enhance therapeutic responses of cisplatin in MCF7 breast cancer cells. The study contributes valuable insights into potential combination therapies, offering a more effective and targeted approach for treating breast cancer.
Supporting Institution
Our project was supported by Bingöl University Scientific Research Projects (BAP) Unit.
Project Number
The Scientific Research Projects Coordination Unit of Bingol University, BAP-SHMYO.2023.001
References
- Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet [Internet]. 2021;397(10286):1750–69. Available from: http://dx.doi.org/10.1016/S0140-6736(20)32381-3
- Smolarz B, Zadrożna Nowak A, Romanowicz H. Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature). Cancers (Basel). 2022;14(10):1–27.
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020 : GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 2021;71(3):209–49.
- Dasari S, Bernard Tchounwou P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364–78.
- Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem [Internet]. 2019;88(March):102925. Available from: https://doi.org/10.1016/j.bioorg.2019.102925
- Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol 2010;28(7):1145–53.
- Sre M, Ml W, Sj E, Beith J, Rf D, Goodwin A, et al. Platinum-based chemotherapy for early triple-negative breast cancer. Cochrane Database Syst Rev 2023;(9):1–147.
- Weimer AK, Demidov D, Lermontova I, Beeckman T, Van Damme D. Aurora kinases throughout plant development. Trends Plant Sci 2016;21(1):69–79.
- Vader G, Lens SMA. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta (BBA)Reviews Cancer. 2008;1786(1):60–72.
- Fu J, Bian M, Jiang Q, Zhang C. Roles of aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007;5(1):1–10.
- Portella G, Passaro C, Chieffi P. Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer. Curr Med Chem 2011;18(4):482–96.
- Richie CT, Golden A. Chromosome Segregation : Aurora B Gets Tousled. 2022;15(10):1–8.
- Libertini S, Abagnale A, Passaro C, Botta G, Portella G. Aurora A and B Kinases - Targets of Novel Anticancer Drugs. Recent Pat Anticancer Drug Discov 2010;5(3):219–41.
- Bavetsias V, Linardopoulos S. Aurora kinase inhibitors: Current status and outlook. Front Oncol 2015;5(DEC):1–2.
- Ma HT, Poon RYC. Aurora kinases and DNA damage response. Mutat Res Fund Mol Mech Mutagen 2020;821.
- Borah NA, Reddy MM. Aurora kinase B inhibition: A potential therapeutic strategy for cancer. Molecules. 2021;26(7):1–30.
- Gundogdu R, Erdogan MK, Sever A, Toy Y. Synergistic effect of RAD50 downregulation on combination of rucaparib and doxorubicin. Ege J Med 2023;62(2):289–300.
- Franken NAPP, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc [Internet]. 2006 Dec 21 [cited 2018 Dec 5];1(5):2315–9. Available from: http://www.nature.com/doifinder/10.1038/nprot.2006.339
- 19. Bettoun A, Joffre C, Zago G, Surdez D, Vallerand D, Gundogdu R, et al. Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation. Oncotarget. 2016;7(28):44142–60.
- Kadir Erdogan M, Halil Gecibesler I, Yapar Y, Gundogdu R, Kirici M, Behcet L, et al. Fatty acid composition, enzyme inhibitory effect, antioxidant and anticancer activity of extract from Saponaria prostrata WILLD. subsp. anatolica HEDGE. Bioorg Chem [Internet]. 2021;113(March):105032. Available from: https://doi.org/10.1016/j.bioorg.2021.105032
- 21. Lee A V, Oesterreich S, Davidson NE. MCF-7 Cells - Changing the Course of Breast Cancer Research and Care for 45 Years. J Natl Cancer Inst 2015;107(7):1–4.
- 22. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 2006;
- 23. Rodriguez LG, Wu X, Guan JL. Wound-healing assay. Methods Mol Biol. 2005;99(1):665–706.
- 24. Chaudhry P, Singh M, Parent S, Asselin E. Prostate Apoptosis Response 4 (Par-4), a Novel Substrate of Caspase-3 during Apoptosis Activation. Mol Cell Biol 2012;32(4):826–39.
- 25. Jiang Y, Ji F, Liu Y, He M, Zhang Z, Yang J, et al. Cisplatin-induced autophagy protects breast cancer cells from apoptosis by regulating yes-associated protein. Oncol Rep 2017;38(6):3668–76.
- 26. Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis. Cancer Res 1993;53(17):3976–85.
- 27. McNamee LM, Brodsky MH. P53-independent apoptosis limits DNA damage-induced aneuploidy. Genetics. 2009;182(2):423–35.
- 28. Marchini S, Ciro’ M, Broggini M. p53-Independent caspase-mediated apoptosis in human leukaemic cells is induced by a DNA minor groove binder with antineoplastic activity. Apoptosis. 1999;4(1):39–45.
- 29. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science (80- ). 1998;281(5381):1322–6.
- 30. Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death Differ [Internet]. 2018;25(1):65–80. Available from: http://dx.doi.org/10.1038/cdd.2017.186
- 31. Kaloni D, Diepstraten ST, Strasser A, Kelly GL. BCL-2 protein family: Attractive targets for cancer therapy. Apoptosis. 2023;28(1–2):20–38.
- 32. Kaufmann T, Strasser A, Jost PJ. Fas death receptor signalling: Roles of Bid and XIAP. Cell Death Differ 2012;19(1):42–50.
- 33. Huang D, Huang Y, Huang Z, Weng J, Zhang S, Gu W. Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated aurora B kinase in breast cancer cell lines. Cancer Cell Int [Internet]. 2019;19(1):1–13. Available from: https://doi.org/10.1186/s12935-019-0885-z
- 34. Zeng WF, Navaratne K, Prayson RA, Weil RJ. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 2007;60(2):218–21.
- 35. Nie M, Wang Y, Yu Z, Li X, Deng Y, Wang Y, et al. AURKB promotes gastric cancer progression via activation of CCND1 expression. Aging (Albany NY). 2020;12(2):1304–21.
- 36. Qi G, Ogawa I, Kudo Y, Miyauchi M, Siriwardena BSMS, Shimamoto F, et al. Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 2007;450(3):297–302.
- 37. Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, et al. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 2006;66(3):326 33.
- 38. International BI. Aurora B inhibitor [Internet]. 2024 [cited 2024 Jan 1]. Available from: https://www.opnme.com/molecules/aurb-bi831266
- 39. Larsen SL, Yde CW, Laenkholm AV, Rasmussen BB, Duun-Henriksen AK, Bak M, et al. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer. BMC Cancer. 2015;15(1):1–15.
Details
| Primary Language | English |
|---|---|
| Subjects | Cancer Cell Biology, Molecular Targets |
| Journal Section | Research Articles |
| Authors | |
| Project Number | The Scientific Research Projects Coordination Unit of Bingol University, BAP-SHMYO.2023.001 |
| Publication Date | September 9, 2024 |
| Submission Date | January 10, 2024 |
| Acceptance Date | April 29, 2024 |
| Published in Issue | Year 2024 |