Androjen Duyarlı ve Androjen Duyarsız Prostat Kanser Hücrelerinde Docetaxel ve Abirateron Asetatın Nrf2 Ekspresyonuna Etkileri

Abstract

Amaç: Docetaxel ve Abirateron asetat, özellikle androjen baskılayıcı tedaviye duyarsız prostat kanseri vakaları için tercih edilen ilaçlardır. Normal hücrede antioksidatif özellik gösteren Nrf2 proteini kanser hücresini de apoptozisten koruyarak hücrede tedaviye yanıtsızlık oluşturmaktadır. Bu çalışmada in vitro koşullarda insan prostat kanser hücrelerine Docetaxel ve Abiraterone asetat uygulamasının Nrf2 ekspresyonu üzerine etkisinin araştırılması amaçlandı. Araçlar ve Yöntem: Androjene cevap veren ve vermeyen olmak üzere iki farklı prostat kanser hücre hattı kullanıldı. Kontrol, AA (Abirateron Asetat), DTX (Dosetaksel) ve AA+DTX olmak üzere 4 grup oluşturuldu. Abirateron asetat ve Docetaxel ile hücreler 72saat süreyle kültüre edildi. Akabinde Nrf2 ekspresyonu değişimi immünofloresan ve Western blot yöntemleri ile incelendi. Bulgular: LNCaP hücrelerinde, Nrf2 kontrol ve AA grubuna kıyasla DTX ve DTX+AA gruplarında azaldı. Kontrol grubu ile AA gruplarında Nrf2 ekspresyon düzeyinde farklılık yoktu. PC3 hücreleri AA ve AA+DTX grupları Nrf2 ekspresyonunda kontrol ve DTX gruplarına göre anlamlı bir artış gözlendi. Kontrol ve DTX gruplarının Nrf2 ekspresyonları benzerdi. Sonuç: Nrf2 proteininin ekspresyon değişimleri her iki hücre hattında da gözlemlenmiştir. Androjen duyarlı prostat kanseri hücrelerinde Docetaxel’in Nrf2 ekspresyonunu baskılayarak kemoterapötik etkinliği artırabileceği ve kanser hastalarında mortalite oranını düşürebileceği öngörülmüştür. Androjen duyarsız hücrelerde ise Abirateron asetatın uygulanması Nrf2 ekspresyonunu artıracağından ilaçlara direnç gelişimine yol açarak tedavinin etkinliğini azaltabileceği öngörülmüştür.

Keywords

• abirateron asetat
• antioksidan
• dosetaksel
• kemoterapi
• LNCaP

Effects of Docetaxel and Abiraterone Acetate on Nrf2 Expression in Androgen-Sensitive and Androgen-Insensitive Prostate Cancer Cells

Abstract

Purpose: Docetaxel and Abiraterone acetate are the drugs of choice, especially for cases of prostate cancer that are insensitive to androgen deprivation therapy. Nrf2, which has antioxidative properties in normal cells, also protects cancer cells from apoptosis, causing the cells to be unresponsive to treatment. This study aimed to investigate the effect of Docetaxel and Abiraterone acetate administration to human prostate cancer cells on Nrf2 expression in vitro. Materials and Methods: Two different prostate cancer cell lines were used: androgen-responsive and non-androgen-responsive. 4 groups were formed as control, AA (Abiraterone Acetate), DTX (Docetaxel), and AA+DTX. Cells were cultured with abiraterone acetate and Docetaxel for 72 hours. Then, Nrf2 expression changes were examined by immunofluorescence and Western blot methods. Results: In LNCaP cells, Nrf2 was decreased in DTX and DTX+AA groups compared to the control and AA groups. Nrf2 was the same between Control and AA groups. In PC3 cells, Nrf2 was higher in AA and AA+DTX groups compared to Control and DTX groups. Nrf2 expressions of the Control and DTX groups were similar. Conclusion: Expression changes of Nrf2 protein were observed in both cell lines. It has been predicted that Docetaxel may increase chemotherapeutic efficacy by suppressing Nrf2 expression in androgen-sensitive prostate cancer cells and may reduce mortality rates in cancer patients. In androgen-insensitive cells, it has been predicted that Abiraterone acetate application may increase Nrf2 expression and decrease the effectiveness of treatment by developing resistance to drugs.

Keywords

• abiraterone acetate
• antioxidant
• chemotherapy
• docetaxel
• LNCaP

References

1. 1. Foreman KJ, Marquez N, Dolgert A, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet. 2018;392(10159):2052–2090.
2. 2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12–49.
3. 3. Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primers. 2021;7(1):9.
4. 4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.
5. 5. Berish RB, Ali AN, Telmer PG, Ronald JA, Leong HS. Translational models of prostate cancer bone metastasis. Nat Rev Urol. 2018;15(7):403–421.
6. 6. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180–1192.
7. 7. Yamada Y, Beltran H. The treatment landscape of metastatic prostate cancer. Cancer Lett. 2021;519:20–29.
8. 8. Henriquez I, Roach M III, Morgan TM, Bossi A, Gomez JA, Abuchaibe O, Counago F. Current and emerging therapies for metastatic castration-resistant prostate cancer (mCRPC). Biomedicines. 2021;9(9):1247.

9. 9. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–1520.
10. 10. Ritch CR, Cookson MS. Advances in the management of castration resistant prostate cancer. BMJ. 2016;355:i4405.
11. 11. Feyerabend S, Saad F, Li T, et al. Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: a network meta-analysis. Eur J Cancer. 2018;103:78–87.
12. 12. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4(4):253–265.
13. 13. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 2014;32(30):3436–3448.
14. 14. Manceau C, Mourey L, Pouessel D, Ploussard G. Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety and efficacy. Expert Rev Anticancer Ther. 2020;20(8):629–638.
15. 15. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34(1):21–43.
16. 16. Mizumura K, Maruoka S, Shimizu T, Gon Y. Role of Nrf2 in the pathogenesis of respiratory diseases. Respir Investig. 2020;58(1):28–35.
17. 17. Tebay LE, Robertson H, Durant ST, et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015;88(Pt B):108–146.
18. 18. Raatikainen S, Aaltomaa S, Karja V, Soini Y. Increased nuclear factor erythroid 2-related factor 2 expression predicts worse prognosis of prostate cancer patients treated with radical prostatectomy. Hum Pathol. 2014;45(11):2211–2217.
19. 19. Kawata H, Kamiakito T, Nakaya T, et al. Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer. J Steroid Biochem Mol Biol. 2017;165(Pt B):219–227.
20. 20. Khurana N, Kim H, Chandra PK, et al. Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: advocating a potent pharmaceutical combination against castration-resistant prostate cancer. Oncol Rep. 2017;38(5):2774–2786.
21. 21. Payandeh Z, Pirpour Tazehkand A, Barati G, et al. Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance. Biochimie. 2020;179:32–45.
22. 22. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12(8):564–571.
23. 23. Jayakumar S, Kunwar A, Sandur SK, Pandey BN, Chaubey RC. Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity. Biochim Biophys Acta. 2014;1840(1):485–494.
24. 24. Tossetta G, Marzioni D. Natural and synthetic compounds in ovarian cancer: a focus on NRF2/KEAP1 pathway. Pharmacol Res. 2022;183:106365.
25. 25. Yang Q, Li K, Huang X, et al. lncRNA SLC7A11-AS1 promotes chemoresistance by blocking SCF(β-TRCP)-mediated degradation of NRF2 in pancreatic cancer. Mol Ther Nucleic Acids. 2020;19:974–985.
26. 26. Dozmorov MG, Hurst RE, Culkin DJ, et al. Unique patterns of molecular profiling between human prostate cancer LNCaP and PC-3 cells. Prostate. 2009;69(10):1077–1090.
27. 27. Soylu H, Kirca M, Avci S, Ozpolat B, Ustunel I. Antiandrogen abiraterone and docetaxel treatments affect Notch1, Jagged1 and Hes1 expressions in metastatic prostate cancer cells. Exp Mol Pathol. 2021;119:104607.
28. 28. Soylu H, Aksu K, Üstünel İ, Karacor K, Beyazçiçek Ö. Abiraterone and docetaxel treatments increase phospho-PTEN expression in metastatic prostate cancer cells. Sağlık Bil Değer. 2023;13(1):6–10.
29. 29. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45.
30. 30. Taguchi K, Yamamoto M. The KEAP1–NRF2 system in cancer. Front Oncol. 2017;7:85.
31. 31. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58(5–6):262–270.
32. 32. Mancini MCS, Morelli AP, Severino MB, et al. Knockout of NRF2 triggers prostate cancer cell death through ROS modulation and sensitizes to cisplatin. J Cell Biochem. 2022;123(12):2079–2092.
33. 33. Hao B, Miao Z, Yuan Y. Clinical significance of Nrf2 expression in benign prostatic hyperplasia and prostate cancer tissues. Int J Clin Exp Pathol. 2016;9(1):118–123.
34. 34. Funes JM, Henderson S, Kaufman R, et al. Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival. Mol Cancer. 2014;13:20.
35. 35. Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–232.