Oral antidiyabetik metforminin hepatosellüler kanser hücreleri üzerine etkisi

Amaç: Bu çalışmada oral antidiyabetik metforminin 4 farklı dozda ve 4 farklı saat aralığında insan hepatosellüler kanser hücre hattında (Hep3B) hücre canlılığı üzerine etkisi araştırılmıştır.Gereç ve Yöntem: Çalışmada Hep3B hücre hattı kullanılmıştır. Metforminin farklı dozlarda ve farklı zaman aralıklarında oluşturduğu sitotoksik etkinin belirlenmesi için 0.5, 1, 5 ve 10 mM dozunda metformine 3, 6, 24 ve 48 saat süreyle maruz kalan Hep3B hücrelerine MTT testi uygulanmıştır. Sonuçlar istatistiksel olarak analiz edilerek yorumlanmıştır. Metforminin doza ve zamana spesifik hücre proliferasyonu üzerine etkisi belirlenmiştir.Bulgular: Metforminin Hep3B hücre hattında hücre proliferasyonu üzerine 3., 6. ve 48. saatlerde kontrol grubuna göre herhangi bir etkisi görülmezken, 24. saatte 5 ve 10mM dozlarında hücre proliferasyonunda azalış gözlenmiştir. Sonuç: Metformin Hep3B hücre hattına farklı zaman aralıklarında ve farklı dozlarda uygulanmış ve hücre canlılığı üzerindeki etkisi MTT testi ile belirlenmiştir. 24 saatte, 5 mM ve 10 mM dozlarda metformin uygulanan Hep3B hücrelerinde proliferasyonun istatistiksel olarak anlamlı bir şekilde azaldığı gözlenmiştir. Diğer zaman aralıklarında ve dozlarda hücre canlılığı üzerinde herhangi bir etki gözlenmemiştir.

Anahtar Kelimeler:

Karaciğer Kanseri, Metformin, Hep3B, Sitotoksisite

Effects of oral antidiabetic metformin on hepatocellular cancer cells

Purpose: In this study, the effects of the oral antidiabetic metformin on cell proliferation on human hepatocellular carcinoma cell line (Hep3B) at 4 different doses and at 4 different time intervals were determined.Materials and Methods: Hep3B cell line was used in this study. The cytotoxic effects of metformin on the Hep3B cells at 4 different doses (0.5, 1, 5 10 mM) and at 4 different time intervals (3, 6, 24 and 48 hours) were determined. The results were statistically analyzed. The dose and time specific effects of metformin on cell proliferation was determined.Results: While metformin did not affect the cell proliferation of Hep3B cells at 3, 6 and 48 h groups according to the control group, the rate of cell proliferation was decreased at 5 mM and 10 mM doses and at 24 h.Conclusion: Metformin was administered on Hep3B cells at different time intervals and at different doses and its effect on cell viability was determined by MTT assay. The cell proliferation and viability of the Hep3B cells were significantly dereased at 5 mM and 10 mM doses and at 24 h. No effect was observed on cell viability at other time intervals and at other doses.

Keywords:

Liver Cancer, Metformin, Hep3B, Cytotoxicity,

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1. Erstad DJ, Tanabe KK. Hepatocellular carcinoma: early-stage management challenges." J Hepatocell Carcinoma. 2017;4:81-92
2. Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med. 2008;132:1761-1766.
3. Tanaka K, Tsuji I, Tamakoshi A, Matsuo K, Ito H, Wakai K et al. Obesity and liver cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol. 2012;42:212-21.
4. Sirtori C R., Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res. 1994;30:187-228.
5. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El- Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case–control study. Gut. 2005;54:533–9.
6. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460-8.
7. Wang Z, Olumi AF. Diabetes, growth hormone- insulin-like growth factor pathways and association to benign prostatic hyperplasia. Differentiation. 2011;82:261-71.
8. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66:10269-73.
9. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:6745-52.
10. Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and cancer. Rev Diabet Stud. 2013;10:228-35.
11. Chen Z, Miao L, Gao X, Wang G, Xu Y. Effect of obesity and hyperglycemia on benign prostatic hyperplasia in elderly patients with newly diagnosed type 2 diabetes. Int J Clin Exp Med. 2015;8:11289- 94.
12. Wang Z, Xiao X, Ge R, Li J, Johnson CW, Rassoulian C et al. Metformin inhibits the proliferation of benign prostatic epithelial cells. PloS One. 2017;12:e0173335.
13. Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int. 2010:30:750-8.
14. Cauchy F, Mebarki M, Leporq B, Laouirem S, Albuquerque M, Lambert S et al.Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis. Clin Sci. 2017;131:27- 36.
15. Guo Z, Cao M, You A, Gao J, Zhou H. Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30. Cancer Sci. 2016;107:507-13.
16. Ling S, Song L, Fan N, Feng T, Liu L, Yang X et al. Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway. Int J Oncol. 2017;50:297-309.
17. Xin HW, Ambe CM, Miller TC, Chen JQ, Wiegand GW, Anderson AJ et al. Liver label retaining cancer cells are relatively resistant to the reported anti- cancer stem cell drug metformin. J Cancer. 2016;7:1142-51.
18. Bost F1, Sahra IB, Le Marchand-Brustel Y, Tanti JF. Metformin and cancer therapy. Curr Opin Oncol. 2012;24:103-8.