Investigation of the Effects of Metformin and Ifosfamide Applications on Cell Proliferation and Apoptosis in Hepatocellular Carcinoma Cells

Year 2024, Volume: 3 Issue: 1, 17 - 24, 23.07.2024

Betül Nur Güney Halime Topal Kızıloğlu Kübra Solak Derya Ulusoy Adem Kara

Abstract

Cancer is a concern, for health ranking as the second leading cause of death after cardiovascular diseases. Among types of cancers hepatocellular carcinoma (HCC) is particularly noteworthy being the most common type following lung and stomach cancers. Various treatment approaches are used for managing HCC like chemotherapy. In this study the HepG2 cancer cell line was used as a model to investigate the effects of ifosfamide and metformin on cancer cells. Cell viability tests and RT PCR analysis targeting genes associated with the PI3K/AKT/mTOR pathway were conducted to evaluate these effects. These results offer valuable insights for advancing further research for their potential application in the treatment not only of HCC but also of other cancer types.

Keywords

Hepatocellular Cancer, Metformin, Ifosfamide, Cell Proliferation, PI3K/AKT/mTOR pathway

References

• 1. Huang DQ, Singal AG, Kanwal F, Lampertico P, Buti M, Sirlin CB, Nguyen MH and Loomba R. Hepatocellular carcinoma surveillance - utilization, barriers and the impact of changing aetiology. Nature Reviews Gastroenterology & Hepatology. 2023; 20;797-809.
• 2. Chidambaranathan – Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Advances in Cancer Research. 2021;149;1-61.
• 3. Brown ZJ, Tsilimigras DI, Ruff SM. Management of Hepatocellular Carcinoma. JAMA Surgery. 2023;158;4;410-420.
• 4. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73;51;4-13.
• 5. Behranvand N, Nasri F, Emameh RZ, Khani P, Hosseini A, Garssen J and Falak R. Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunology, Immunotherapy. 2022;71;507-526.
• 6. Idle JR, Beyoğlu D. Ifosfamide - History, efficacy, toxicity and encephalopathy. Pharmacology & Therapeutics. 2023;243;108366.
• 7. Ugwueze CV, Ogamba OZ, Young EE, Onyenekwe BM and Ezeokpo BC. Metformin: A Possible Option in Cancer Chemotherapy. Analytical Cellular Pathology. 2020.
• 8. Rizos CV, Elisaf MS. Metformin and cancer. European Journal of Pharmacology. 2013;705;1;3;96-108.
• 9. Winston CA, Jiang AA, Shuen Toh EM, Han C, Ong ZH, Peng S, Tham HY, Sundar R, Chong CS and Khoo CM. Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression. International Journal of Colorectal Disease. 2020;35;1501-1512.
• 10. Özakyol A. Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology). Journal of Gastrointestinal Cancer. 2017;48;238-240.
• 11. Grazie ML, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: The present and the future. World Journal of Hepatology. 2017;9;21;907-920.
• 12. Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Japanese Journal of Clinical Oncology. 2017;48;2;103-114.
• 13. Ahn HK, Lee YH and Koo KC. Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review. International Journal of Molecular Sciences. 2020;21;22;8540
• 14. Brancher S, Ribeiro AE, Toporcov TN and Weiderpass E. The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials. Journal of Cancer Research and Clinical Oncology. 2021;147;2819-2836.
• 15. De A and Kuppusamy G. Metformin in breast cancer: preclinical and clinical evidence. Current Problems in Cancer. 2020;44;1;100488.
• 16. Xu Y, Che H, Liu J, Ye P. Association of metformin and statin uses with the prognosis of colon cancer: a meta-analysis. European Journal of Cancer Prevention. 2024;33;1.
• 17. Almeida-Nunes DN, Silvestre R, Dinis-Oliveira RJ, Ricardo S. Enhancing Immunotherapy in Ovarian Cancer: The Emerging Role of Metformin and Statins. International Journal of Molecular Sciences. 2023;25;1;323.
• 18. Jing Z, Quan T, Shu-Feng Z, Clinical Pharmacology of Cyclophosphamide and Ifosfamide. Current Drug Therapy. 2006;1;1;30;55-84.
• 19. Furlanut M, Franceschi L, Pharmacology of Ifosfamide. Oncology. 2003;65;2;2-6.
• 20. Buda A, Dell’Anna T, Signorelli M, Mangioni C. Role of Ifosfamide in Cervical Cancer, An Overview. Oncology. 2003;65;2;63-66.
• 21. AlMotwaa SM. Coupling Ifosfamide to nanoemulsion-based clove oil enhances its toxicity on malignant breast cancer and cervical cancer cells. Pharmacia. 2021;68;4;779–787.
• 22. Kumbhar P, Khade V, Khadake V, Marale P, Manjappa A, Nadaf S, Kumbar V, Bhagwat D, Disouza J. Ifosfamide - Loaded Cubosomes: An Approach to Potentiate Cytotoxicity against MDA-MB-231 Breast Cancer Cells. Fabad Journal of Pharmaceutical Sciences. 2023;48;1;37-52.
• 23. Karaagac M, Artac M, Goksu SS, Karakurt Eryilmaz M, Coskun HS, Bozcuk H. Irinotecan and Ifosfamide Combination is an Effective and Safe Option in Patients with Refractory Small Cell Lung Cancer: A Retrospective Cross-Sectional Study. EJMO. 2020;4;2;172-176.
• 24. Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C and Greabu M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. International Journal of Molecular Sciences. 2021;22;1;173.
• 25. Carpenter R and Brady MF. BAX Gene. Europe PMC. 2020;32310387.
• 26. Han H, Li Y, Qin W, Wang L, Yin H, Su B, et al. miR-199b-3p Contributes To Acquired Resistance To Cetuximab İn Colorectal Cancer By Targeting CRIM1 Via Wnt/Β-Catenin Signaling. Cancer Cell International. 2022;22;1;42.
• 27. Zulaeha S, Safarrida A, Suyono A, Hartuti ED, Purwoko D, Tajuddin T. A Simple and Efficient Protocol of RNA Extraction from Apple Leaves (Malus x domestica); A Silica Column-Based Method. International Journal of Agriculture System. 2023;11;1;37-47.