Investigating of Effects of Metformin on Melanoma Skin Cancer

Yıl 2021, , 111 - 115, 30.06.2021

Harun Alp Hidayet Tutun , Levent Altıntaş , Halil Mahir Kaplan , Ergin Şingirik , İbrahim Kahraman

https://doi.org/10.15321/GenelTipDer.2021.295

Öz

Aim: Apoptotic pathways are important for resistance to chemotherapeutics drugs and cancer development. Metformin is a safe, inexpensive and effective drug used to treat type 2 diabetes. Furthermore, although there is evidence of anticancer effects, the mechanisms by which metformin exerts this effect are unclear. If metformin is thought to be safe, cheap and effective drugs, the potentially beneficial effects of these drugs are of great importance. Therefore, it was aimed to investigate Bcl-2, kaspaz-3, bax, wee-1, AIF, grp78 and gadd153 levels in metformin treated skin cancer cells.

Materials and Methods: For this propose we prepared culture of skin cancer cells then these cells were treated with metformin and it was analyzed kaspase-3, bcl-2, wee 1, gadd153, grp78 and AIF protein levels by ELISA on these cells.

Result: Treatment of metformin increased of proapoptotic proteins (kaspase-3, bcl-2, wee 1, gadd153, grp78 and AIF) and decreased antiapoptotic protein (bcl-2).

Conclusion: In conclusion, our study showed that metformin has apoptotic effect on melanoma skin cancer.

Anahtar Kelimeler

Metformin, Melanoma skin cancer, kaspase-3, bcl-2, wee 1

Metforminin Melanom Cilt Kanseri Hücreleri Üzerindeki Etkisinin Araştırılması

Öz

Amaç: Kanserlerde kemoterapötiklere gösterilen dirençte ve kanser gelişiminde apoptozisin önemli rolü vardır. Metformin tip 2 diyabet tedavisinde kullanılan güvenli, ucuz ve etkili bir ilaçtır. Ayrıca, antikanser etkilerinin olduğuna dair kanıtlar olmasına rağmen metforminin bu etkiyi hangi mekanizmalar ile gerçekleştirdiği açık değildir. Bu nedenle, çalışmamızda cilt kanseri hücrelerine metformin uygulamasının Bcl-2, kaspaz-3, bax, wee-1, AIF, grp78 ve gadd153 düzeyleri üzerine etkileri araştırıldı.

Gereç ve Yöntem: İlgili protein düzeylerinin belirlenmesinde ELISA testleri kullanıldı.

Bulgular: Çalışmamızda metforminin cilt kanseri hücrelerinde apoptozis proteinlerini (kaspaz-3, wee 1, gadd153, grp78 ve AIF) arttırdığı ve antiapoptotik markırı (bcl-2) azalttığı belirlendi.

Sonuç: Sonuç olarak çalışmamız; metforminin melanom cilt kanseri üzerine apoptotik etkisinin olduğunu göstermiştir.

Anahtar Kelimeler

Metformin, Melanom cilt kanseri, kaspaz-3, bcl-2, wee 1

Kaynakça

• Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes Int 2004; 21: 115.
• Del Barco S, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J. et al. Metformin: multi-faceted protection against cancer. Oncotarget 2011; 2: 896-917.
• Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci 2012; 122 (6): 253-270.
• Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle 2010; 9 (6): 1057-1064.
• Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304-1305.
• Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011; 11:20. doi: 10.1186/1471-2407-11-20.
• Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32: 1620-1625.
• Pulito C, Donzelli S, Muti P, Puzzo L, Strano S, Blandino G. microRNAs and cancer metabolism reprogramming: the paradigm of metformin. Ann Transl Med 2014; 2 (6): 58.
• Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 1816):926-945.
• Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin–dependent translation initiation in breast cancer cells. Cancer Research 2007; 67 (22): 10804-10812.
• Han G, Gong H, Wang Y, Guo S, Liu K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther 2015; 16 (1): 77-87.
• Honjo S, Ajani JA, Scott AW, Chen Q, Skinner HD, Stroehlein J. et al. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol 2014; 45 (2): 567-574.
• Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11: 390-401.
• Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO. et al. Metformin: taking away the candy for cancer? Eur J Cancer 2010; 46 (13): 2369-2380.
• Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 2005; 1 (1): 15-25.
• Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J. et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation 2001; 108 (8): 1167-1174.
• Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE. et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009; 8 (6): 909-915.
• Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase–dependent growth inhibitor for breast cancer cells. Cancer Research 2006; 66 (21): 10269-10273.
• Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 2009; 8: 88-96.
• Nelson LE, Valentine RJ, Cacicedo JM, Gauthier MS, Ido Y, Ruderman NB. A novel inverse relationship between metformin-triggered AMPKSIRT1 signaling and p53 protein abundance in high glucoseexposed HepG2 cells. Am J Physiol Cell Physiol 2012; 303: C4-C13. doi: 10.1152/ajpcell.00296.2011.
• Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F. et al. Metformin blocks melanoma invasion and metastasis development in AMPK/ p53-dependent manner. Mol Cancer Ther 2013; 12: 1605-1615.
• Li P, Zhao M, Parris AB, Feng X, Yang X. p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochem Biophys Res Commun 2015; 464 (4): 1267-1274.
• Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M, Gotlieb WH. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecologic Oncology 2011; 121 (3): 492-498.
• Mossman T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65 (1-2): 55-63.
• Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528: 262–266.
• Preiss D, Dawed A, Welsh P, Heggie A, Jones AG, Dekker J. et al. Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. Diabetes Obes Metab 2017; 19: 356-363.
• Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494: 256-260.
• Malek M, Aghili R, Emami Z, Khamseh ME. Risk of cancer in diabetes: the effect of metformin. ISRN Endocrinology, 2013.
• Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29: 254-258.
• Landman GW, Kleefstra N, van Haterenm KJJ, Groenier KH, Gans ROB, Bilo HJG. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 2010; 33: 322-326.
• Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B. et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res 2010; 3 (11): 1451-1461.
• Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomarkers Prev 2009; 18: 701-705.
• Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol 2009; 27: 3271-3273.
• Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case–control analysis. Gynecologic Oncology 2011; 123 (2): 200-204.
• Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67 (14): 6745-6752.
• Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy. Gynecologic Oncology 2010; 116 (1): 92-98.
• Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J et al. Metforminin- take is associated with better survival in ovarian cancer:A case-controlstudy. Cancer 2013; 119: 555-562.
• Lee DJ, Kim B, Lee JH, Park SJ, Hong SP, Cheon JH. et al. The effect of metformin on responses to chemotherapy and survival instage iv colorectal cancer with diabetes. Korean J Gastroenter 2013; 60: 355-361.
• Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res 2010; 3: 1066-1076.
• Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012; 18: 2905-2912.
• Fang Z, Xu X, Zhou Z, Xu Z, Liu Z. Effect of metformin on apoptosis, cell cycle arrest migration and invasion of A498 cells. Molecular Medicine Reports 2014; 9 (6): 2251-2256.
• Patel S, Singh N, Kumar L. Evaluation of effects of metformin in primary ovarian cancer cells. Asian Pac J Cancer Prev 2015; 16 (16): 6973-6979.
• Queiroz EA, Puukila S, Eichler R, Sampaio SC, Forsyth HL, Lees SJ. et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PloS one 2014; 9 (5): e98207.
• Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clinical Cancer Research 2009; 15 (4): 1126-1132.
• Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281 (5381): 1322-1326.
• Tomic T, Botton T, Cerezo M, Robert G, Luciano F, Puissant A. et al. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death & Disease 2011; 2 (9): e199.
• Do K, Doroshow JH, Kummar S. Wee1 kinase as a target for cancer therapy. Cell Cycle 2013; 12 (19): 3348-3353.
• Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death and Differentiation 1999; 6 (6): 516.
• Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC. et al. Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Research 2015; 32 (5): 1627-1637.
• Tsai CC, Chuang TW, Chen LJ, Niu HS, Chung KM, Cheng JT. et al. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells. World Journal of Gastroenterology 2015; 21 (14): 4169.
• Ma L, Wei J, Wan J, Wang W, Wang L, Yuan Y. et al. Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways. Journal of Experimental & Clinical Cancer Research 2019; 38 (1): 77.
• Wu N, Gu C, Gu H, Hu H, Han Y, Li Q. Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153. Neoplasma 2011; 58 (6): 482-490.