3-(2-Carboxyethyl)phenylboronic Acid ve 4-Aminocarbonylphenylboronic Acid Bileşiklerinin Parental ve Bortezomib-Dirençli Prostat Kanseri Hücre Hatlarındaki Etkileri

Abstract

Kemoterapi kanser tedavisinde yaygın olarak kullanılan bir metod olmakla birlikte hücrelerin zamanla kemoterapötik ilaçlara karşı direnç oluşturması (kemoresistans) önemli bir sorun oluşturmaktadır. Bortezomib çeşitli kanser türlerinin tedavisinde kullanılan bor elementi içeren bir bileşiktir. Ancak pek çok çalışmada bortezomib muamelesine cevap olarak hücrelerde hızlı bir şekilde direnç oluştuğu gösterilmiştir. Bu çalışmada PC3 insan prostat kanseri hücre hattı (PC3-Parental) ve daha önceki çalışmalarda bortezomib direnci kazandırılmış PC3 hücre hatları (PC3-Dirençli) kullanılmıştır. Çalışma kapsamında PC3-Parental ve PC3-Dirençli hücreler üzerinde diğer bazı bor içeren bileşiklerin sitotoksik etkileri araştırılmıştır. 48 saat süreyle 3-(2-Carboxyethyl)phenylboronic acid ile muamele sonrasında IC₅₀ değeri, PC3-Parental hücrelerde 702.7 µM; PC3-Dirençli hücrelerde ise 1156 µM olarak tespit edilmiştir. 4-Aminocarbonylphenylboronic acid bileşiğinin 48 saat muamele sonrasında IC₅₀ değeri, PC3-Parental hücrelerde 117.3 µM; PC3-Dirençli hücrelerde ise 226.3 µM olarak bulunmuştur. Özellikle 4-Aminocarbonylphenylboronic acid bileşiği daha düşük bir IC₅₀ değerine sahip olduğu için, daha detaylı analizler ile etkilerinin araştırılması faydalı olacaktır. Ayrıca, farklı ilaç kombinasyonu denemeleri ile daha düşük konsantrasyonlarda daha etkili bir kanser tedavi yaklaşımı geliştirilebileceği düşünülmektedir.

Keywords

• 3-(2-Carboxyethyl)phenylboronic acid
• 4-Aminocarbonylphenylboronic acid
• bortezomib
• prostat kanseri

The Effects of 3-(2-Carboxyethyl)phenylboronic Acid and 4-Aminocarbonylphenylboronic Acid Compounds on Parental and Bortezomib-Resistant Prostate Cancer Cell Lines

Abstract

Although chemotherapy is a widely used method in cancer treatment, the development of resistance to chemotherapeutic agents over time (chemoresistance) constitutes a major problem. Bortezomib is a boron element-containing compound used in the treatment of various cancer types. However, many studies have demonstrated that cells rapidly develop resistance in response to bortezomib treatment. In this study, the PC3 human prostate cancer cell line (PC3-Parental) and previously established bortezomib-resistant PC3 cell lines (PC3-Resistant) were used. Within the scope of the study, the cytotoxic effects of several other boron-containing compounds were investigated on PC3-Parental and PC3-Resistant cells. After 48 hours of treatment with 3-(2-Carboxyethyl)phenylboronic acid, the IC₅₀ value was determined as 702.7 µM in PC3-Parental cells and 1156 µM in PC3-Resistant cells. Following 48 hours of treatment with 4-Aminocarbonylphenylboronic acid, the IC₅₀ values were found to be 117.3 µM in PC3-Parental cells and 226.3 µM in PC3-Resistant cells. Since 4-Aminocarbonylphenylboronic acid exhibited a lower IC₅₀ value, further detailed analyses would be beneficial to investigate its effects more comprehensively. Additionally, it is thought that a more effective cancer treatment strategy at lower concentrations could be developed through trials of different drug combinations.

Keywords

• 3-(2-Carboxyethyl)phenylboronic acid
• 4-Aminocarbonylphenylboronic acid
• bortezomib
• prostate cancer

References

1. [1] R. W. Ruddon, “Cancer Biology”. Fourth Edition, Oxford University Press, 530 p, 2007.
2. [2] X. Guan, “Cancer metastases: challenges and opportunities”. Acta Pharmaceutica Sinica B, 5(5), 402-418, 2015.
3. [3] A. Yerlikaya, E. Okur, “An investigation of the mechanisms underlying the proteasome inhibitor bortezomib resistance in PC3 prostate cancer cell line”. Cytotechnology, 72(1), 121-130, 2020.
4. [4] H. Zahreddine, K. L. Borden, “Mechanisms and insights into drug resistance in cancer”. Frontiers in Pharmacology, 4, 28, 2013.
5. [5] L. Chen, K. Madura, “Increased proteasome activity, ubiquitin-conjugating enzymes, and eEF1A translation factor detected in breast cancer tissue”. Cancer Research, 65(13), 5599-5606, 2005.
6. [6] J. Adams, “The proteasome as a novel target for the treatment of breast cancer”. Breast Disease, 15, 61-70, 2002.
7. [7] A. Yerlikaya, N. Erin, “Differential sensitivity of breast cancer and melanoma cells to proteasome inhibitor velcade”. International Journal of Molecular Medicine, 22(6), 817-823, 2008.
8. [8] M. Escobar, M. Velez, A. Belalcazar, E. S. Santos, L. E. Raez, “The role of proteasome inhibition in nonsmall cell lung cancer”. Journal of Biomedicine and Biotechnology, 2011, 806506, 2011.

9. [9] E. Okur, A. Yerlikaya, “A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis”. Cell Biology and Toxicology, 35(1), 33-47, 2019.
10. [10] J. Adams, “The development of proteasome inhibitors as anticancer drugs”. Cancer Cell, 5, 417-421, 2004.
11. [11] S. N. Markovic, S. M. Geyer, F. Dawkins, W. Sharfman, M. Albertini, W. Maples, P. M. Fracasso, T. Fitch, P. Lorusso, A. A. Adjei, C. Erlichman, “A phase II study of bortezomib in the Ttreatment of metastatic malignant melanoma”. Cancer, 103, 2584-2589, 2005.
12. [12] D. J. Kuhn, E. L. Zeger, R. Z. Orlowski, “Proteasome inhibitors and modulators of heat shock protein function”. Update on Cancer Therapeutics I, 91-116, 2006.
13. [13] L. Y. Schumacher, D. D. Vo, H. J. Garban, B. Comin-Anduix, S. K. Owens, V. B. Dissette, J. A. Glaspy, W. H. McBride, B. Bonavida, J. S. Economou, A. Ribas, “Immunosensitization of tumor cells to dentritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, velcade)”. The Journal of Immunology, 176, 4757-4765, 2006.
14. [14] P. Queirolo, M. Acquati, “Targeted therapies in melanoma”. Cancer Treatment Reviews, 32(7), 524-531, 2006.
15. [15] Z. H. Tang, Y. L. Wu, S. L. Gao, H. W. Shen, “Effects of the proteasome inhibitor bortezomib on gene expression profiles of pancreatic cancer cells”. Journal of Surgical Research, 145, 111-12, 2008.
16. [16] R. Oerlemans, N. E. Franke, Y. G. Assaraf, J. Cloos, I. Van Zantwijk, C. R. Berkers, G. L. Scheffer, K. Debipersad, K. Vojtekova, C. Lemos, J. W. Van Der Heijden, B. Ylstra, G. J. Peters, G. L. Kaspers, B. A. C. Dijkmans, R. J. Scheper, G. Jansen, “Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein”. Blood, 112(6), 2008.
17. [17] Y. X. Wu, J. H. Yang, H. Saitsu, “Bortezomib-resistance is associated with increased levels of proteasome subunits and apoptosis-avoidance”. Oncotarget, 7, 77622-77634, 2016.
18. [18] P. D. Baade, D. R. Youlden, L. J. Krnjacki, “International epidemiology of prostate cancer: geographical distribution and secular trends”. Molecular Nutrition and Food Research, 53, 2, 171-184, 2009.
19. [19] D. G. Bostwick, H. B. Burke, D. Djakiew, S. Euling, S. M. Ho, J. Landolph, H. Morrison, B. Sonawane, T. Shifflett, D. J. Waters, B. Timms, “Human prostate cancer risk factors”. Cancer, 101(S10), 2371-2490, 2004.
20. [20] A. Chlenski, K. I. Nakashiro, K. V. Ketels, G. I. Korovaitseva, R. Oyasu, “Androgen receptor expression in androgen-independent prostate cancer cell lines”. Prostate, 47(1), 66-75, 2001.
21. [21] G. Buchanan, P. S. Craft, M. Yang, A. Cheong, J. Prescott, L. Jia, G. A. Coetzee, W. D. Tilley, “PC-3 cells with enhanced androgen receptor signaling: a model for clonal selection in prostate cancer”. Prostate, 60(4), 352-366, 2004.
22. [22] O. S. Mohammad, M. D. Nyquist, M. T. Schweizer, S. P. Balk, E. Corey, S. Plymate, P. S. Nelson, E. A. Mostaghel, “Supraphysiologic testosterone therapy in the treatment of prostate cancer: models, mechanisms and questions”. Cancers, 9(12), 166, 2017.
23. [23] I. V. Litvinov, L. Antony, S. L. Dalrymple, R. Becker, L. Cheng, J. T. Isaacs, “PC3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor”. The Prostate, 66(12), 1329-1338, 2006.
24. [24] C. A. Martins, G. D. G. Rocha, C. R. Gattass, C. M. Takiya, “Pomolic acid exhibits anticancer potential against a docetaxel‑resistant PC3 prostate cell line”. Oncology Reports, 42(1), 328-338, 2019.
25. [25] S. T. Nawrocki, J. S. Carew, K. Dunner, L. H. Boise, P. J. Chiao, P. Huang, J. L. Abbruzzese, D. J. McConkey, “Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells”. Cancer Research, 65(24), 11510-11519, 2005.
26. [26] S. Şeker, B. Şahin, A. Yerlikaya, “Comparative analysis of acquired resistance to bortezomib in prostate cancer cells using proteomic and bioinformatic tools”. Journal of Cellular and Molecular Medicine, 29(1), e70254, 2025.
27. [27] A. Yerlikaya, E. Okur, S. Şeker, N. Erin, “Combined effects of the proteasome inhibitor bortezomib and Hsp70 inhibitors on the B16F10 melanoma cell line”. Molecular Medicine Reports, 3(2), 333-339, 2010.
28. [28] A. Yerlikaya, S. Altıkat, R. Irmak, F. Z. Çavga, S. A. Kocacan, İ. Boyacı, “Effect of bortezomib in combination with cisplatin and 5 fluorouracil on 4T1 breast cancer cells”. Molecular Medicine Reports, 8(1), 277-281, 2013.
29. [29] Ş. A. Düzgün, A. Yerlikaya, S. Zeren, Z. Bayhan, E. Okur, İ. Boyacı, “Differential effects of p38 MAP kinase inhibitors SB203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line”. Cytotechnology, 69(4), 711-724, 2017.
30. [30] B. Aras, A. Yerlikaya, “Bortezomib and etoposid combinations exert synergistic effects on PC-3 prostate cancer line”. Oncology Letters, 11, 3179-3184, 2016.
31. [31] https://pubchem.ncbi.nlm.nih.gov/compound/3856118
32. [32] D. Jiang, M. Zheng, X. Yan, B. Huang, H. Huang, T. Gong, K. Liu, J. Liu, “A “turn-on” ESIPT fluorescence probe of 2-(aminocarbonyl)phenylboronic acid for the selective detection of Cu(ii)”. RSC Advances, 12(48), 31186-31191, 2022.
33. [33] A. Paramore, S. Frantz, “Bortezomib”. Nature Reviews Drug Discovery, 2(8), 611-612, 2003.
34. [34] A. Yerlikaya, E. Tümer, M. Güzel, “Comparative investigation of cytotoxic effects of structurally diverse small molecules and in silico analysis of 1-Acetyl-4-(4-Hydroxyphenyl)piperazine”. Journal of Cellular and Molecular Medicine, 30(1), e70890, 2026.