Volume 35, Issue 1 (April 2024)
Studies in Medical Sciences 2024, 35(1): 1-9 |
Back to browse issues page
Research code: 62201
Ethics code: IR.TBZMED.REC.1394.795
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Shafiei-Irannejad V, Zarghami N, Samadi N, Akbarzadeh A. EXAMINING THE EFFECT OF METFORMIN ON ENHANCING THE SENSITIVITY OF CISPLATIN-RESISTANT OVARIAN CANCER CELLS (A2780/CP). Studies in Medical Sciences 2024; 35 (1) :1-9
URL: http://umj.umsu.ac.ir/article-1-6207-en.html
URL: http://umj.umsu.ac.ir/article-1-6207-en.html
Assistant Professor of Clinical Biochemistry, Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran (Corresponding Author) , vahid.shafiei@hotmail.com
Abstract: (1637 Views)
Background & Aims: Cancer is considered as one of the main causes of death and a major health challenge in the world. Resistance to chemotherapy is one of the challenges in this field. Some recent findings have shown that anti-diabetic drugs, especially metformin, when combined with anticancer drugs, produce positive effects in cancer treatment. In the present study, the activity and possible mechanism of the effect of metformin in increasing the sensitivity of ovarian carcinoma cell line A2780/CP to cisplatin were investigated.
Materials & Methods: In this experimental study, ovarian cancer cells resistant to cisplatin (A2780/CP) were selected. The effect of metformin on cisplatin cytotoxicity was evaluated using MTT method. The mRNA expression levels of multidrug resistant-associated protein 2 (MRP-2) after metformin treatment were determined using reverse transcription polymerase chain reaction (RT-PCR). The effect of metformin on cisplatin-induced apoptosis was investigated using the Annexin V/FITC method. All data were analysed using GraphPad Prism 6.01, and p value < 0.05 were considered as significant.
Results: Metformin increased the cytotoxic effects of cisplatin in cisplatin-resistant A2780/CP ovarian cancer cells, but had no effect on the cytotoxicity of sensitive A2780 ovarian cancer cells. Metformin had no effect on MRP-2 gene expression. In addition, metformin increased the apoptotic effects of cisplatin in A2780/CP cells.
Conclusion: The results of the present study showed that metformin increases the sensitivity of A2780/CP cells to the cytotoxic effects of cisplatin. Therefore, metformin may be an effective and potent compound for combination therapy in ovarian cancer cells to overcome multidrug resistance to chemotherapy agents.
Materials & Methods: In this experimental study, ovarian cancer cells resistant to cisplatin (A2780/CP) were selected. The effect of metformin on cisplatin cytotoxicity was evaluated using MTT method. The mRNA expression levels of multidrug resistant-associated protein 2 (MRP-2) after metformin treatment were determined using reverse transcription polymerase chain reaction (RT-PCR). The effect of metformin on cisplatin-induced apoptosis was investigated using the Annexin V/FITC method. All data were analysed using GraphPad Prism 6.01, and p value < 0.05 were considered as significant.
Results: Metformin increased the cytotoxic effects of cisplatin in cisplatin-resistant A2780/CP ovarian cancer cells, but had no effect on the cytotoxicity of sensitive A2780 ovarian cancer cells. Metformin had no effect on MRP-2 gene expression. In addition, metformin increased the apoptotic effects of cisplatin in A2780/CP cells.
Conclusion: The results of the present study showed that metformin increases the sensitivity of A2780/CP cells to the cytotoxic effects of cisplatin. Therefore, metformin may be an effective and potent compound for combination therapy in ovarian cancer cells to overcome multidrug resistance to chemotherapy agents.
Type of Study: Research |
Subject:
فارماکولوژی
References
1. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E. Cancer treatment and survivorship statistics, 2012. Cancer J Clin 2012;62(4):220-41. [DOI:10.3322/caac.21149] [PMID]
2. Morrison J, Haldar K, Kehoe S, Lawrie TA. Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev 2012;2012(8):Cd005343. [DOI:10.1002/14651858.CD005343.pub3]
3. Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer 2005;15 Suppl 1:3-11. [DOI:10.1136/ijgc-00009577-200505001-00002] [PMID]
4. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999;39:361-98. [DOI:10.1146/annurev.pharmtox.39.1.361] [PMID]
5. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000;11(4):265-83. [DOI:10.1016/S0928-0987(00)00114-7] [PMID]
6. Gottesman MM, Ambudkar SV. Overview: ABC transporters and human disease. J Bioenerg Biomembr 2001;33(6):453-8. [DOI:10.1023/A:1012866803188] [PMID]
7. Yousefi B, Samadi N, Baradaran B, Shafiei-Irannejad V, Zarghami N. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies. Chem Biol Drug Des 2016;88(1):17-25. [DOI:10.1111/cbdd.12737] [PMID]
8. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455(1):152-62. [DOI:10.1016/0005-2736(76)90160-7]
9. Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 1983;221(4617):1285-8. [DOI:10.1126/science.6137059] [PMID]
10. Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pirker R, Green A, Crist W, Brodeur GM, et al. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 1989;81(2):116-24. [DOI:10.1093/jnci/81.2.116] [PMID]
11. Gottesman MM, Ling V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 2006;580(4):998-1009. [DOI:10.1016/j.febslet.2005.12.060] [PMID]
12. Zhang Z, Tan S, Feng SS. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials 2012;33(19):4889-906. [DOI:10.1016/j.biomaterials.2012.03.046] [PMID]
13. Edgerton DS, Johnson KM, Cherrington AD. Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. Front Biosci 2009;14(3):1169-81. [DOI:10.2741/3301] [PMID]
14. Bikman BT, Zheng D, Kane DA, Anderson EJ, Woodlief TL, Price JW, Dohm GL, Neufer PD, Cortright RN. Metformin Improves Insulin Signaling in Obese Rats via Reduced IKKbeta Action in a Fiber-Type Specific Manner. J Obes 2010;2010. [DOI:10.1155/2010/970865] [PMID] []
15. Zheng J, Woo SL, Hu X, Botchlett R, Chen L, Huo Y, Wu C. Metformin and metabolic diseases: a focus on hepatic aspects. Front Med 2015;9(2):173-86. [DOI:10.1007/s11684-015-0384-0] [PMID] []
16. Lee JM, Seo WY, Song KH, Chanda D, Kim YD, Kim DK, Lee MW, Ryu D, Kim YH, Noh JR, Lee CH, Chiang JY, Koo SH, Choi HS. AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner. J Biol Chem 2010;285(42):32182-91. [DOI:10.1074/jbc.M110.134890] [PMID] []
17. Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, Pasanisi P, Pilotti S. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2013;32(12):1475-87. [DOI:10.1038/onc.2012.181] [PMID]
18. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline Chemotherapy and Cardiotoxicity. Cardiovasc Drugs Ther 2017;31(1):63-75. PMC5346598. 10.1007/s10557-016-6711-0 [DOI:10.1007/s10557-016-6711-0] [PMID] []
19. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science 1997;278(5340):1064-8. [DOI:10.1126/science.278.5340.1064] [PMID]
20. Burger H, Foekens JA, Look MP, Meijer-van Gelder ME, Klijn JG, Wiemer EA, Stoter G, Nooter K. RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res 2003;9(2):827-36. [Google Scholar]
21. Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 2004;11(3):537-51. [DOI:10.1677/erc.1.00800] [PMID] []
22. Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 2001;10(7):705-13. [DOI:10.1093/hmg/10.7.705] [PMID]
23. Urquhart BL, Tirona RG, Kim RB. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol 2007;47(5):566-78. [DOI:10.1177/0091270007299930] [PMID]
24. Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007;63(1):12-31. [DOI:10.1016/j.critrevonc.2007.02.001] [PMID]
25. Jamali B, Nakhjavani M, Hosseinzadeh L, Amidi S, Nikounezhad N, F HS. Intracellular GSH Alterations and Its Relationship to Level of Resistance following Exposure to Cisplatin in Cancer Cells. Iran J Pharm Res 2015;14(2):513-9. [PMID]
26. Kurokawa H, Nishio K, Ishida T, Arioka H, Fukuoka K, Nomoto T, Fukumoto H, Yokote H, Saijo N. Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene. Jpn J Cancer Res 1997;88(2):108-10. [DOI:10.1111/j.1349-7006.1997.tb00354.x] [PMID] []
27. Oguri T, Isobe T, Suzuki T, Nishio K, Fujiwara Y, Katoh O, Yamakido M. Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int J Cancer 2000;86(1):95-100. https://doi.org/10.1002/(SICI)1097-0215(20000401)86:1<95::AID-IJC15>3.0.CO;2-G
https://doi.org/10.1002/(SICI)1097-0215(20000401)86:1<95::AID-IJC15>3.0.CO;2-G [DOI:10.1002/(SICI)1097-0215(20000401)86:13.0.CO;2-G]
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
