Prostat kanseri modelinde metformin ve matriks metalloproteinaz ilişkisine doğrudan bir köprü: oksidatif stress

Amaç: Çalışmanın amacı, prostat kanseri modelinde metforminin etkisinin yanı sıra Matriks metalloproteinaz2 (MMP2) ve oksidatif stres parametrelerinin olası rolünü belirlemekti. Gereç ve Yöntem: Erkek Copenhagen sıçanları üç gruba ayrıldı. Kontrol grubu, kanser grubu, kanser+metformin (CM) grubu. Prostat kanseri, 2x104 Mat-LyLu hücrelerinin subkutan enjeksiyonu ile oluşturuldu. Metformin tedavisi, Mat- Lylu hücrelerinin ardından gavaj yoluyla günlük olarak uygulandı. Mat-LyLu hücre enjeksiyonunu takiben 14. günde deney sonlandırıldı.. Enzyme Linked Immuno Sorbent Assay (ELISA) yöntemi kullanılarak serum glutatyon (GSH), prostat spesifik antijen (PSA) ve malondialdehit (MDA) düzeyleri belirlendi. Ayrıca serum matriks metalloproteinaz 2 (MMP) 2 aktiviteleri ELISA aracılığıyla belirlendi. Bulgular: GSH, CM grubunda kanser grubuna göre önemli ölçüde arttı. PSA, MDA ve MMP2, CM grubunda kanser grubuna göre anlamlı derecede düşüktü. Oksidatif stres parametreleri kanser grubunda anlamlı olarak yüksek bulundu. Metformin GSH, PSA, MDA ve MMP2 gibi parametrelerdeki kanser etkisini tersine döndürdü. Sonuç: Prostat kanser modelinin MMP ve oksidatif stres parametreleri üzerine zararlı bir etkiye neden olduğunu ve metformin uygulamasının da kanserin neden olduğu değişiklikleri iyileştirdiği saptandı. Metforminin etki mekanizmasını prostat kanseri kaynaklı serbest radikal ürünlerini inhibe ettiği ve antioksidan kapasiteyi değiştirerek gösterdiği belirlendi. Metformin, terapötik kanser tedavi sürecindeki potansiyel bir anti kanser ilacı olmaya adaydır.

Anahtar Kelimeler:

matriks metalloproteinaz, metformin, prostat kanser, sıçan, oksidatif stress

A direct bridge to metformin and matrix metalloproteinase relationship in prostate cancer model: oxidative stress

Purpose: The purpose of the study was to evaluate the effect of metformin as well as the possible role of Matrix metalloproteinase2 (MMP2) and oxidative stress parameters on the prostate cancer model. Materials and Methods: Male Copenhagen rats were divided into three groups. Control group, cancer group, cancer+metformin (CM) group. 2x104 Mat-LyLu cells were inoculated subcutaneously to generate prostate cancer. Metformin treatment was administered daily by gavage following inoculation of the Mat- Lylu cells. The experiment was terminated on the 14th day following Mat-LyLu cell injection. Serum glutathione (GSH), prostate-specific antigen (PSA), and malondialdehyde (MDA) levels were determined by employing the Enzyme-Linked ImmunoSorbent Assay (ELISA) method. In addition, the serum matrix metalloproteinase (MMP) 2 activities were determined via ELISA. Results: GSH was significantly increased in the CM group than in the cancer group. PSA, MDA and MMP2 were significantly lower in the CM group than in the cancer group. Oxidative stress parameters were significantly higher in the cancer group. Metformin reversed cancer’s effect in GSH, PSA, MDA, and MMP2 parameters. Conclusion: Prostate cancer model caused a detrimental effect on MMP and oxidative stress parameters, and metformin administration ameliorated the changes caused by cancer. Metformin showed its mechanism of action by inhibiting free radical products originating from prostate cancer and changing the antioxidant capacity. Metformin is a candidate to be a potential anticancer drug in the therapeutic cancer treatment process.

Keywords:

Matrix metalloproteinase, prostate cancer, rat, metformin, oxidative stress,

PDF

___

1. Dou X, Tong P, Huang H, Zellmer L, He Y, Jia Q et al. Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology. J Cancer. 2020;11:2887–920.
2. 2.Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT Signaling. Int J Mol Sci. 2020; 21:4507.
3. 3.Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF et al. The roles of matrix metalloproteinases and their ınhibitors in human diseases. Int J Mol Sci. 2020;21:9739.
4. Raeeszadeh-Sarmazdeh, D. Do ML, Hritz BG. Metalloproteinases and their ınhibitors: potential for the development of new therapeutics. Cells 2020;9:1313.
5. Soydinç HA, Çamlıca H, Duranyıldız D, Sağlam EK, Taş F, Yasasever V et al. Matriks metalloproteinazlar ve akciğer kanseri. Turk J Oncol. 2006;21:53-6.
6. Napoli S, Scuderi C, Gattuso G, Bella VD, Candido S, Basile MS et al. Functional roles of matrix metalloproteinases and their ınhibitors in melanoma. Cells. 2020;9:1151.
7. Zhang F, Chen H, Du J, Wang B, Yang L. Anticancer activity of metformin, an antidiabetic drug, against ovarian cancer cells involves inhibition of cysteineRich 61 (Cyr61)/Akt/Mammalian target of rapamycin (mTOR) signaling pathway. Med Sci Monit. 2018;24:6093-101.
8. Júnior ADH, Bragagnoli AC, Costa FO and Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol. 2021;27:1883–904.
9. Bugan I, Karagoz Z, Altun S, Djamgoz MBA. Gabapentin, an analgesic used against cancerassociated neuropathic pain: Effects on prostate cancer progression in an in vivo rat model. Basic Clin. Pharmacol. Toxicol. 2016;118:200–207.
10. Koroglu-Aydın P, Bayrak BB, Bugan I, KarabulutBulan O, Yanardag R. Histological and biochemical investigation of the renoprotective effects of metformin in diabetic and prostate cancer model. Toxicol Mech Methods. 2021;31:489-500.
11. Mossine V, Chopra P, Mawhinney TP. Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res. 2008;68:4384-81.
12. Niland S, Riscanevo AX, Eble JA. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci. 2021;23:146.
13. Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol. 2021;27:1883-904.
14. Ahn HK, Lee YH, Koo KC. Current status and application of metformin for prostate cancer: a comprehensive review. Int J Mol Sci. 2020;21:8540.
15. Kumar NP, Moideen K, Viswanathan V, Shruthi BS, Sivakumar S, Menon PA et al. Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard antituberculosis or metformin treatment. BMC Infect Dis. 2018;18:345.
16. Gong Y, Chippada-Venkata UD, K Oh W. Roles of matrix metalloproteinases and their natural inhibitors in prostate cancer progression. Cancers (Basel). 2014;6:1298-327.
17. Oguić R, Mozetič V, Tešar EC, Čupić DF, Mustać E, Dorđević G. Matrix metalloproteinases 2 and 9 immunoexpression in prostate carcinoma at the positive margin of radical prostatectomy specimens. Pathol Res Int. 2014;2014:262195.
18. Feng X, Pan J, Li J, Zeng C, Qi W, Shao Y et al. Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/Mtor. Aging (Albany NY). 2020;12:1087– 103.
19. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.
20. Li YR, Halliwill KD, Adams CJ, Iyer V, Riva L, Mamunur R, et al. Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice. Nat Commun. 2020;11:394.
21. Chio IIC, Tuveson DA. ROS in cancer: the burning question. Trends Mol Med. 2017;23:411-29.
22. Rašić I, Rašić A, Akšamija G, Radović S. The relationshıp between serum level of malondialdehyde and progression of colorectal cancer. Acta Clin Croat. 2018;57:411-6.
23. Han C, Wang Z, Xu Y, et al. Roles of reactive oxygen species in biological behaviors of prostate cancer. Biomed Res Int. 2020;2020:1269624.
24. Aljofan M, Riethmacher D. Anticancer activity of metformin: a systematic review of the literature. Future Sci OA. 2019;5:FSO410.
25. Sun X, Zhu MJ. AMP-activated protein kinase: a therapeutic target in intestinal diseases. Open Biol. 2017;7:170104.
26. Ahn HK, Lee YH, Koo KC. Current status and application of metformin for prostate cancer: a comprehensive review. Int J Mol Sci. 2020;21:854.