Document Type : Original Article(s)

Author

Department of Molecular Biology, Iraqi Center for Cancer and Medical Genetics Research, Mustansiriyah University, Baghdad, Iraq

Abstract

Background: Glioblastoma (GBM) stands out as the most prevalent primary brain tumor characterized by its high aggressiveness. Numerous therapeutic approaches have been employed, and the utility of combination therapies has been substantiated, particularly in GBM treatment. Cisplatin, an anticancer chemotherapeutic agent, is employed for the management of various malignancies, including GBM; however, it is associated with significant systemic toxicity. In the realm of combination therapy, metformin, a biguanide drug conventionally used as a first-line treatment for type 2 diabetes, has recently emerged as a valuable adjunct in the treatment of a diverse spectrum of tumors. This study aimed to elucidate the impact of metformin on sensitizing the human cerebral GBM cancer cell line (AMGM) to cisplatin chemotherapy by employing the comet assay as a means to assess DNA damage, thereby advocating the potential of metformin as an adjuvant for cisplatin-based therapy.
Method: In this experimental study, the AMGM cell line was cultured and subsequently treated with either single-agent cisplatin, metformin, or a combination of both drugs. Cell viability was assessed through growth inhibition calculations. The Chou–Talalay analysis was used to assess the cooperative effect of this drug combination. Furthermore, DNA fragmentation was quantified using the alkaline comet assay technique.
Results: The findings demonstrate that metformin significantly potentiates the therapeutic efficacy of cisplatin by synergistically inhibiting the growth of AMGM cells and reducing DNA damage.
Conclusion: These results underscore the potential utility of metformin as a valuable adjunct in enhancing the clinical effectiveness of chemotherapy regimens.

Highlights

Zaynab Abdulghany (Google Scholar)

Keywords

Main Subjects

How to cite this article:

Abdulghany ZS. Metformin enhances the sensitivity of glioblastoma cancer cells to cisplatin through DNA damage assessment. Middle East J Cancer. 2024;15(2):98-107. doi: 10.30476/mejc.2023.98580.1905.

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi: 10.3322/caac.21660.
  2. Iraqi Cancer Board. Annual Report, Iraqi Cancer Registry 2021. Iraqi Cancer Board, Ministry of Health and Environment, Republic of Iraq; 2022. 306 p. Available from: https://moh.gov.iq/upload/1691449545.pdf
  3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi: 10.3322/caac.21654. Erratum in: CA Cancer J Clin. 2021;71(4):359.
  4. Yimit A, Adebali O, Sancar A, Jiang Y. Differential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs. Nat Commun. 2019;10(1):309. doi: 10.1038/s41467-019-08290-2.
  5. Moretton A, Slyskova J, Simaan ME, Arasa-Verge EA, Meyenberg M, Cerrón-Infantes DA, et al. Clickable cisplatin derivatives as versatile tools to probe the DNA damage response to chemotherapy. Front Oncol. 2022;12:874201. doi: 10.3389/fonc.2022.874201.
  6. Fung C, Dinh P Jr, Ardeshir-Rouhani-Fard S, Schaffer K, Fossa SD, Travis LB. Toxicities associated with cisplatin-based chemotherapy and radiotherapy in long-term testicular cancer survivors. Adv Urol. 2018;2018:8671832. doi: 10.1155/2018/8671832.
  7. Chovanec M, Abu Zaid M, Hanna N, El-Kouri N, Einhorn LH, Albany C. Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann Oncol. 2017;28(11):2670-9. doi: 10.1093/annonc/mdx360.
  8. 2. Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes International. 2004;21(3):115-7. doi:10.1002/pdi.606.
  9. Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011; 9: 33. doi:10.1186/1741-7015-9-33.
  10. 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(4):6745-52. doi: 10.1158/0008-5472.CAN-06-4447.
  11. Ugwueze CV, Ogamba OJ, Young EE, Onyenekwe BM, Ezeokpo BC. Metformin: a possible option in cancer chemotherapy. Anal Cell Pathol (Amst). 2020;2020:7180923. doi: 10.1155/2020/7180923.
  12. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res. 2019; 11:3295-313. doi: 10.2147/CMAR.S200059.
  13. Mazurek M, Litak J, Kamieniak P, Kulesza B, Jonak K, Baj J, et al. Metformin as potential therapy for high-grade glioma. Cancers (Basel). 2020;12(1):210. doi: 10.3390/cancers12010210
  14. Ohno M, Kitanaka C, Miyakita Y, Tanaka S, Sonoda Y, Mishima K, et al. Metformin with temozolomide for newly diagnosed glioblastoma: results of phase I Study and a brief review of relevant studies. Cancers (Basel). 2022;14:4222. doi: 10.3390/cancers14174222.
  15. Seliger C, Luber C, Gerken M, Schaertl J, Proescholdt M, Riemenschneider MJ, et al. Use of metformin and survival of patients with high-grade glioma. Int J Cancer. 2019;144(2):273-80. doi: 10.1002/ijc.31783.
  16. Liu EK, Vasudevaraja V, Sviderskiy VO, Feng Y, Tran I, Serrano J, et al. Association of hyperglycemia and molecular subclass on survival in IDH-wildtype glioblastoma. Neurooncol Adv. 2022;4(1):vdac163. doi: 10.1093/noajnl/vdac163.
  17. Al-Shammari AM, Al-Juboory AA, Al-Mukhtar AA, Ali AM, Al-Hili ZA, Yaseen NY. Abstract 1221: Establishment and characterization of a chemoresistant glioblastoma cell line from an Iraqi patient. Cancer Res. 2014;74(19_Supplement): 1221. doi:10.1158/1538-7445.AM2014-1221.
  18. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 1984;22:27-55. doi:10.1016/0065-2571(84)90007-4.
  19. Collins AR. The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol. 2004;26(3):249-61. doi: 10.1385/MB:26:3:249.
  20. Chakravarty M, Ganguli P, Murahari M, Sarkar RR, Peters GJ, Mayur YC. Study of combinatorial drug synergy of novel acridone derivatives with temozolomide using in-silico and in-vitro methods in the treatment of drug-resistant glioma. Front Oncol. 2021;11:625899. doi:10.3389/fonc.2021.625899.
  21. Ohno M, Kitanaka C, Miyakita Y, Tanaka S, Sonoda Y, Mishima K, et al. Metformin with temozolomide for newly diagnosed glioblastoma: Results of phase I study and a brief review of relevant studies. Cancers (Basel). 2022;14(17):4222. doi: 10.3390/cancers14174222.
  22. Zou Y, Wang Y, Xu S, Liu Y, Yin J, Lovejoy DB, et al. Brain co-delivery of temozolomide and cisplatin for combinatorial glioblastoma chemotherapy. Adv Mater. 2022;34(33):e2203958. doi: 10.1002/adma.202203958.
  23. Al Hassan M, Fakhoury I, El Masri Z, Ghazale N, Dennaoui R, El Atat O, et al. Metformin treatment inhibits motility and invasion of glioblastoma cancer cells. Anal Cell Pathol (Amst). 2018;2018:5917470. doi: 10.1155/2018/5917470.
  24. Apostolou P, Toloudi M, Kourtidou E, Mimikakou G, Vlachou I, Chatziioannou M, et al. Use of the comet assay technique for quick and reliable prediction of in vitro response to chemotherapeutics in breast and colon cancer. J Biol Res (Thessalon). 2014;21(1):14. doi: 10.1186/2241-5793-21-14.