Erkan ARSLAN, Ebru TEMİZ, Şükrü AKMEŞE, Nihayet BAYRAKTAR, İsmail KOYUNCU

Cisplatin’in Normal ve Prostat Kanseri Hücrelerinin Aminoasit Metabolizması Üzerine Etkileri

Amaç: Erkek üreme sistemini etkileyen bir kanser türü olan prostat kanseri, dünya genelinde en sık görülen ikinci kanser türü olup, erkeklerde tüm kanserlerin %10'unu oluşturmaktadır. Prostat kanseri hastalarında kullanılan birincil tedavi yöntemlerinden biri kemoterapidir. Cisplatin, prostat kanseri başta olmak üzere birçok kanser türünün tedavisinde yaygın olarak kullanılan bir kemoterapi ilacı olup, DNA replikasyonu ve transkripsiyon süreçlerine müdahale ederek etki gösterir. Fakat kanser hücrelerinde cisplatine karşı gelişen ilaç direnci ve normal hücreler üzerindeki yan etkiler bu ilacın kullanımı kısıtlayıp tedavi verimini azaltmaktadır. Son zamanlarda kanser hücrelerinde cisplatine karşı gelişen direncin “metabolik yeniden programlama” kaynaklı olduğu edilmiştir. Bu nedenle metabolik süreçleri hedeflemek, cisplatin direncini tersine çevirmek için potansiyel yeni bir stratejiyi temsil eder. Materyal ve Metod: Bu nedenle bu çalışma cisplatinin kanserli ve normal prostat hücrelerinin aminoasit metobolizması üzerindeki etkilerinin incelenmiştir. Çalışmada prostat kanseri hücresi (DU-145) ve normal prostat hücrelerine (PNT-1A) besi ortamında 10 µM cisplatin uygulanıp 24 saat inkübe edildi. Elde edilen hücre lizatındaki serbest aminoasit profili LC-MS/MS yöntemiyle incelendi. Verilerin analizi SPSS ve metaboanalist 5.0 programı ile yapıldı. Bulgular: Cisplatin uygulanan PNT1A hücrelerinde arginin miktarı azalırken, Taurin, fosfo etonalamin, ornitin ve triptofan seviyesinin arttığı gözlendi. Cisplatin uygulanan DU-145 hücrelerinde ise arginin, glisin ve 2-Aminoheptandioik Asit miktarının arttığı, sarkozin ve beta alanin ise azaldığı tespit edildi. Sonuç: Çalışma sonucunda cisplatin normal ve kanser hücrelerin aminoasit metabolizması üzerinde faklı etkiler gösterdiği, bu nedenle farklılık gösteren aminoasitlerin invitro ortamda uygulanarak yeni çalışmaların yapılması, kanser tedavisinde olumlu etkiler oluşturabilir.

Anahtar Kelimeler:

Prostat kanseri, Cisplatin, Aminoasit Metabolizması, Metabolomik

Effects of Cisplatin on Amino Acid Metabolism of Normal and Prostate Cancer Cells

Background: Prostate cancer, which is a type of cancer affecting the male reproductive system, is the second most common type of cancer worldwide and constitutes 10% of all cancers in men. One of the primary treatment methods used in prostate cancer patients is chemotherapy. Cisplatin is a chemotherapy drug widely used in the treatment of many types of cancer, especially prostate cancer, and it acts by interfering with DNA replication and transcription processes. However, drug resistance against cisplatin in cancer cells and side effects on normal cells limit its use and reduce the treatment efficiency. Recently, resistance to cisplatin in cancer cells has been reported to be due to "metabolic reprogramming". Targeting metabolic processes therefore represents a potential new strategy to reverse cisplatin resistance. Materials and Methods: This study investigates the effects of cisplatin on amino acid metabolism of cancerous and normal prostate cells. In the study, 10 µM cisplatin was applied to prostate cancer cells (DU-145) and normal prostate cells (PNT-1A) in the medium and incubated for 24 hours. The free amino acid profile in the obtained cell lysate was analyzed by LC-MS/MS method. Data analysis was done with SPSS and metaboanalyst 5.0 program. Results: While the amount of arginine decreased in the PNT1A cells treated with cisplatin, the levels of taurine, phosphoethonalamine, ornithine and tryptophan were increased. It was determined that the amount of arginine, glycine and 2-Aminoheptandioic Acid increased, while sarcosine and beta alanine decreased in DU-145 cells when treated with cisplatin. Conclusions: As a result of the study, cisplatin has different effects on amino acid metabolism of normal and cancer cells, therefore, new studies by applying different amino acids in vitro may have positive effects in cancer treatment.

Keywords:

Prostate cancer, Cisplatin, Amino acid Metabolism,

PDF

___

1. Zhu W, Li Y, Gao L. Cisplatin in combination with programmed cell death protein 5 increases antitumor activity in prostate cancer cells by promoting apoptosis. Molecular Medicine Reports. 2015;11(6):4561-6.
2. Thomsen FB, Brasso K, Klotz LH, Røder MA, Berg KD, Iversen P. Active surveillance for clinically localized prostate cancer––A systematic review. Journal of surgical oncology. 2014;109(8):830-5.
3. van den Bergh RC, Albertsen PC, Bangma CH, Freedland SJ, Graefen M, Vickers A, et al. Timing of curative treatment for prostate cancer: a systematic review. European urology. 2013;64(2):204-15.
4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.
5. Wilkins LJ, Tosoian JJ, Sundi D, Ross AE, Grimberg D, Klein EA, et al. Surgical management of high-risk, localized prostate cancer. Nature Reviews Urology. 2020;17(12):679-90.
6. Powers E, Karachaliou GS, Kao C, Harrison MR, Hoimes CJ, George DJ, et al. Novel therapies are changing treatment paradigms in metastatic prostate cancer. Journal of hematology & oncology. 2020;13(1):1-13.
7. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nature Reviews Cancer. 2015;15(12):701-11.
8. Huang H, Li P, Ye X, Zhang F, Lin Q, Wu K, et al. Isoalantolactone Increases the Sensitivity of Prostate Cancer Cells to Cisplatin Treatment by Inducing Oxidative Stress. Frontiers in Cell and Developmental Biology. 2021:809.
9. Pignot G, Maillet D, Gross E, Barthelemy P, Beauval J-B, Constans-Schlurmann F, et al. Systemic treatments for high-risk localized prostate cancer. Nature reviews Urology. 2018;15(8):498-510.
10. Rottenberg S, Disler C, Perego P. The rediscovery of platinum-based cancer therapy. Nature Reviews Cancer. 2021;21(1):37-50.
11. Su F, Ahn S, Saha A, DiGiovanni J, Kolonin MG. Adipose stromal cell targeting suppresses prostate cancer epithelial-mesenchymal transition and chemoresistance. Oncogene. 2019;38(11):1979-88.
12. de Porras VR, Wang XC, Palomero L, Marin-Aguilera M, Solé-Blanch C, Indacochea A, et al. Taxane-induced attenuation of the CXCR2/BCL-2 axis sensitizes prostate cancer to platinum-based treatment. European urology. 2021;79(6):722-33.
13. Valentovic MA. Evaluation of resveratrol in cancer patients and experimental models. Advances in cancer research. 2018;137:171-88.
14. Wang L, Zhao X, Fu J, Xu W, Yuan J. The role of tumour metabolism in cisplatin resistance. Frontiers in Molecular Biosciences. 2021;8:691795.
15. Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. Journal of experimental & clinical cancer research. 2015;34(1):1-10.
16. Biswas SK. Metabolic reprogramming of immune cells in cancer progression. Immunity. 2015;43(3):435-49.
17. van der Mijn JC, Panka DJ, Geissler AK, Verheul H, Mier JW. Novel drugs that target the metabolic reprogramming in renal cell cancer. Cancer & metabolism. 2016;4(1):1-18.
18. Li C, Zhang G, Zhao L, Ma Z, Chen H. Metabolic reprogramming in cancer cells: glycolysis, glutaminolysis, and Bcl-2 proteins as novel therapeutic targets for cancer. World journal of surgical oncology. 2015;14(1):1-7.
19. Sun L, Suo C, Li S-t, Zhang H, Gao P. Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2018;1870(1):51-66.
20. Akmeşe Ş, Temiz E, Koyuncu İ, Taşkıran H, Tüysüz MZ. Farklı Meme Kanseri Hücre Hatlarında Karnitin Metabolizmasının İncelenmesi. Harran Üniversitesi Tıp Fakültesi Dergisi. 2022;19(1):1-7.
21. Wei Z, Liu X, Cheng C, Yu W, Yi P. Metabolism of amino acids in cancer. Frontiers in cell and developmental biology. 2021;8:603837.
22. Melchini A, Traka MH. Biological profile of erucin: a new promising anticancer agent from cruciferous vegetables. Toxins. 2010;2(4):593-612.
23. Arslan E, Koyuncu I. Comparison of Amino Acid Metabolisms in Normal Prostate (PNT-1A) and Cancer Cells (PC-3). Oncologie. 2021;23(1).
24. Yoo H-C, Han J-M. Amino Acid Metabolism in Cancer Drug Resistance. Cells. 2022;11(1):140.