Skip to main content
SpringerLink
Log in

Mechanisms of cancer cell killing by metformin: a review on different cell death pathways

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All information was inserted in the manuscript and new data generated.

References

  1. Wang L-H, Wu C-F, Rajasekaran N, Shin YK (2018) Loss of tumor suppressor gene function in human cancer: an overview. Cell Physiol Biochem 51(6):2647–2693

    Article  CAS  Google Scholar 

  2. Jimbo H, Nagai H, Fujiwara S, Shimoura N, Nishigori C (2020) Fas-FasL interaction in cytotoxic T cell-mediated vitiligo: the role of lesional expression of tumor necrosis factor-α and interferon-γ in Fas-mediated melanocyte apoptosis. Exp Dermatol 29(1):61–70

    Article  CAS  Google Scholar 

  3. Mu Q, Najafi M (2021) Modulation of the tumor microenvironment (TME) by melatonin. Eur J Pharmacol 907:174365. https://doi.org/10.1016/j.ejphar.2021.174365

    Article  CAS  Google Scholar 

  4. Farhood B, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Musa AE, Najafi M (2020) TGF-β in radiotherapy: mechanisms of tumor resistance and normal tissues injury. Pharmacol Res 155:104745

    Article  CAS  Google Scholar 

  5. Mu Q, Najafi M (2021) Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells. Int Immunopharmacol 98:107895. https://doi.org/10.1016/j.intimp.2021.107895

    Article  CAS  Google Scholar 

  6. Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z (2019) Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med 23(8):4854–4865

    Article  Google Scholar 

  7. Srinivas US, Tan BW, Vellayappan BA, Jeyasekharan AD (2019) ROS and the DNA damage response in cancer. Redox Biol 25:101084

    Article  CAS  Google Scholar 

  8. Zou Z, Chang H, Li H, Wang S (2017) Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis 22(11):1321–1335

    Article  CAS  Google Scholar 

  9. Fu X, Li M, Tang C, Huang Z, Najafi M (2021) Targeting of cancer cell death mechanisms by resveratrol: a review. Apoptosis 2021:1–13

    Google Scholar 

  10. Liu T, Zhang J, Li K, Deng L, Wang H (2020) Combination of an autophagy inducer and an autophagy inhibitor: a smarter strategy emerging in cancer therapy. Front Pharmacol 11:408

    Article  CAS  Google Scholar 

  11. Long K, Suresh K (2020) Pulmonary toxicity of systemic lung cancer therapy. Respirology 25:72–79

    Article  Google Scholar 

  12. Fu X, He Y, Li M, Huang Z, Najafi M (2021) Targeting of the tumor microenvironment by curcumin. BioFactors. https://doi.org/10.1002/biof.1776

    Article  Google Scholar 

  13. Kasznicki J, Sliwinska A, Drzewoski J (2014) Metformin in cancer prevention and therapy. Ann Transl Med 2(6):57

    Google Scholar 

  14. Wu Z, Zhang C, Najafi M (2021) Targeting of the tumor immune microenvironment by metformin. J Cell Commun Signal. https://doi.org/10.1007/s12079-021-00648-w

    Article  Google Scholar 

  15. Zhuang Y, Miskimins WK (2011) Metformin induces both caspase-dependent and poly (ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol Cancer Res 9(5):603–615

    Article  CAS  Google Scholar 

  16. Bailey CJ (2017) Metformin: historical overview. Diabetologia 60(9):1566–1576

    Article  CAS  Google Scholar 

  17. Zhang L, He H, Balschi JA (2007) Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. https://doi.org/10.1152/ajpheart.00002.2007

    Article  Google Scholar 

  18. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C et al (2016) Anti-Inflammatory effects of metformin irrespective of diabetes status. Circ Res 119(5):652–665. https://doi.org/10.1161/circresaha.116.308445

    Article  CAS  Google Scholar 

  19. Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S (2015) Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes 64(6):2028–2041. https://doi.org/10.2337/db14-1225

    Article  CAS  Google Scholar 

  20. Yahyapour R, Amini P, Saffar H, Rezapoor S, Motevaseli E, Cheki M et al (2018) Metformin protects against radiation-induced heart injury and attenuates the up-regulation of dual oxidase genes following rat’s chest irradiation. Int J Mol Cell Med 7(3):193

    CAS  Google Scholar 

  21. Azmoonfar R, Amini P, Saffar H, Rezapoor S, Motevaseli E, Cheki M, Yahyapour R, Nouruzi F, Khodamoradi E, Shabeeb D, Musa AE (2018) Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression. Adv Pharm Bull 8:697

    Article  CAS  Google Scholar 

  22. Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J et al (2016) Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res 17(1):107. https://doi.org/10.1186/s12931-016-0420-x

    Article  CAS  Google Scholar 

  23. Kelleni MT, Amin EF, Abdelrahman AM (2015) Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol 2015:424813. https://doi.org/10.1155/2015/424813

    Article  CAS  Google Scholar 

  24. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE (2012) Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 22(11):820–827. https://doi.org/10.1097/FPC.0b013e3283559b22

    Article  CAS  Google Scholar 

  25. Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30(5):359–371. https://doi.org/10.2165/00003088-199630050-00003

    Article  CAS  Google Scholar 

  26. Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P et al (2014) Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol (Phila) 52(2):129–135. https://doi.org/10.3109/15563650.2013.860985

    Article  CAS  Google Scholar 

  27. Kanto K, Ito H, Noso S, Babaya N, Hiromine Y, Taketomo Y et al (2017) Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 9(3):587–593. https://doi.org/10.1111/jdi.12755

    Article  CAS  Google Scholar 

  28. Parikh AB, Kozuch P, Rohs N, Becker DJ, Levy BP (2017) Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial. Invest New Drugs 35(6):813–819. https://doi.org/10.1007/s10637-017-0511-7

    Article  CAS  Google Scholar 

  29. Zi F, Zi H, Li Y, He J, Shi Q, Cai Z (2018) Metformin and cancer: an existing drug for cancer prevention and therapy (Review). Oncol Lett 15(1):683–690. https://doi.org/10.3892/ol.2017.7412

    Article  CAS  Google Scholar 

  30. Kim HJ, Lee S, Chun KH, Jeon JY, Han SJ, Kim DJ et al (2018) Metformin reduces the risk of cancer in patients with type 2 diabetes: an analysis based on the Korean National Diabetes Program Cohort. Medicine 97(8):e0036

    Article  CAS  Google Scholar 

  31. Roshan MH, Shing YK, Pace NP (2019) Metformin as an adjuvant in breast cancer treatment. SAGE Open Med 7:2050312119865114

    Article  Google Scholar 

  32. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B (2014) Metformin: from mechanisms of action to therapies. Cell Metab 20(6):953–966

    Article  CAS  Google Scholar 

  33. Turacli ID, Candar T, Yuksel EB, Kalay S, Oguz AK, Demirtas S (2018) Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie 154:62–68

    Article  Google Scholar 

  34. Najafi M, Cheki M, Rezapoor S, Geraily G, Motevaseli E, Carnovale C et al (2018) Metformin: prevention of genomic instability and cancer: a review. Mutat Res 827:1–8. https://doi.org/10.1016/j.mrgentox.2018.01.007

    Article  CAS  Google Scholar 

  35. Ugwueze CV, Ogamba OJ, Young EE, Onyenekwe BM, Ezeokpo BC (2020) Metformin: a possible option in cancer chemotherapy. Anal Cell Pathol. https://doi.org/10.1155/2020/7180923

    Article  Google Scholar 

  36. Riaz MA, Sak A, Erol YB, Groneberg M, Thomale J, Stuschke M (2019) Metformin enhances the radiosensitizing effect of cisplatin in non-small cell lung cancer cell lines with different cisplatin sensitivities. Sci Rep 9(1):1–16

    Article  Google Scholar 

  37. Skinner HD, Crane CH, Garrett CR, Eng C, Chang GJ, Skibber JM et al (2013) Metformin use and improved response to therapy in rectal cancer. Cancer Med 2(1):99–107

    Article  CAS  Google Scholar 

  38. Zhang H-H, Guo X-L (2016) Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol 78(1):13–26

    Article  CAS  Google Scholar 

  39. Huang J, Chang Z, Lu Q, Chen X, Najafi M (2022) Nobiletin as an inducer of programmed cell death in cancer: a review. Apoptosis. https://doi.org/10.1007/s10495-022-01721-4

    Article  Google Scholar 

  40. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B et al (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45(6):487–498

    Article  CAS  Google Scholar 

  41. Sia J, Szmyd R, Hau E, Gee HE (2020) Molecular mechanisms of radiation-induced cancer cell death: a primer. Front Cell Dev Biol 8:41

    Article  Google Scholar 

  42. Kennedy LB, Salama AK (2020) A review of cancer immunotherapy toxicity. CA Cancer J Clin 70(2):86–104

    Article  Google Scholar 

  43. Golden E, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC (2012) The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2:88

    Article  CAS  Google Scholar 

  44. Mortezaee K, Najafi M (2021) Immune system in cancer radiotherapy: resistance mechanisms and therapy perspectives. Crit Rev Oncol Hematol 157:103180. https://doi.org/10.1016/j.critrevonc.2020.103180

    Article  Google Scholar 

  45. Eriksson D, Stigbrand T (2010) Radiation-induced cell death mechanisms. Tumor Biol 31(4):363–372

    Article  Google Scholar 

  46. Prise KM, Schettino G, Folkard M, Held KD (2005) New insights on cell death from radiation exposure. Lancet Oncol 6(7):520–528

    Article  CAS  Google Scholar 

  47. Chaurasia M, Bhatt AN, Das A, Dwarakanath BS, Sharma K (2016) Radiation-induced autophagy: mechanisms and consequences. Free Radic Res 50(3):273–290

    Article  CAS  Google Scholar 

  48. Wang Q, Ju X, Wang J, Fan Y, Ren M, Zhang H (2018) Immunogenic cell death in anticancer chemotherapy and its impact on clinical studies. Cancer Lett 438:17–23

    Article  CAS  Google Scholar 

  49. Kepp O, Galluzzi L, Martins I, Schlemmer F, Adjemian S, Michaud M et al (2011) Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. Cancer Metastasis Rev 30(1):61–69

    Article  CAS  Google Scholar 

  50. Nodooshan SJ, Amini P, Ashrafizadeh M, Tavakoli S, Aryafar T, Khalafi L et al (2020) Suberosin attenuates the proliferation of MCF-7 breast cancer cells in combination with radiotherapy or hyperthermi. Curr Drug Res Rev. https://doi.org/10.2174/2589977512666201228104528

    Article  Google Scholar 

  51. Mortezaee K, Narmani A, Salehi M, Bagheri H, Farhood B, Haghi-Aminjan H et al (2021) Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy/chemotherapy of cancer. Life Sci 269:119020. https://doi.org/10.1016/j.lfs.2021.119020

    Article  CAS  Google Scholar 

  52. Amini P, Nodooshan SJ, Ashrafizadeh M, Eftekhari S-M, Aryafar T, Khalafi L et al (2021) Resveratrol induces apoptosis and attenuates proliferation of MCF-7 cells in combination with radiation and hyperthermia. Curr Mol Med 21(2):142–150

    Article  CAS  Google Scholar 

  53. Suzuki A, Leland P, Joshi BH, Puri RK (2015) Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine 75(1):79–88

    Article  CAS  Google Scholar 

  54. Mortezaee K, Goradel NH, Amini P, Shabeeb D, Musa AE, Najafi M et al (2019) NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr Mol Pharmacol 12(1):50–60

    Article  CAS  Google Scholar 

  55. Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Rezaeyan A, Najafi M (2020) Abscopal effect in radioimmunotherapy. Int Immunopharmacol 85:106663. https://doi.org/10.1016/j.intimp.2020.106663

    Article  CAS  Google Scholar 

  56. Kaur P, Asea A (2012) Radiation-induced effects and the immune system in cancer. Front Oncol 2:191

    Article  CAS  Google Scholar 

  57. Inoue K, Fry EA (2018) Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN network. Cancer Investig 36(9–10):520–536

    Article  Google Scholar 

  58. Saraei P, Asadi I, Kakar MA, Moradi-Kor N (2019) The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manage Res 11:3295

    Article  CAS  Google Scholar 

  59. Saini N, Yang X (2018) Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin 50(2):133–143

    Article  CAS  Google Scholar 

  60. D’Arcy MS (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43(6):582–592

    Article  Google Scholar 

  61. Jan R (2019) Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull 9(2):205

    Article  CAS  Google Scholar 

  62. Yu D-L, Lou Z-P, Ma F-Y, Najafi M (2022) The interactions of paclitaxel with tumour microenvironment. Int Immunopharmacol 105:108555. https://doi.org/10.1016/j.intimp.2022.108555

    Article  CAS  Google Scholar 

  63. Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Najafi M (2020) The interactions and communications in tumor resistance to radiotherapy: therapy perspectives. Int Immunopharmacol 87:106807. https://doi.org/10.1016/j.intimp.2020.106807

    Article  CAS  Google Scholar 

  64. Yaniv B, Sadraei NH, Palackdharry S, Takiar V, Wise-Draper T (2018) Metformin induces pro-tumorigenic cytokines and natural killer cells in patients with locally advanced head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 100(5):1369. https://doi.org/10.1016/j.ijrobp.2017.12.161

    Article  Google Scholar 

  65. Crist M, Lehn M, Wise-Draper T (2021) Abstract 1775: metformin-mediated natural killer cell cytotoxicity in head and neck squamous cell carcinoma. Cancer Res 81(13 Supplement):1775. https://doi.org/10.1158/1538-7445.AM2021-1775

    Article  Google Scholar 

  66. Kim K, Yang WH, Jung YS, Cha JH (2020) A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity. BMB Rep 53(10):512–520. https://doi.org/10.5483/BMBRep.2020.53.10.149

    Article  CAS  Google Scholar 

  67. Verdura S, Cuyàs E, Martin-Castillo B, Menendez JA (2019) Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy. Oncoimmunology 8(10):e1633235-e. https://doi.org/10.1080/2162402X.2019.1633235

    Article  Google Scholar 

  68. Lin Y, Wang S, Bremer E, Zhang H (2021) Harnessing the soil: reshaping the tumor microenvironment towards an antitumor immune state by low-dose metformin. Cancer Commun 41(8):637–641. https://doi.org/10.1002/cac2.12196

    Article  Google Scholar 

  69. Vara JÁF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204

    Article  CAS  Google Scholar 

  70. Yu C, Yang B, Najafi M (2021) Targeting of cancer cell death mechanisms by curcumin; implications to cancer therapy. Basic Clin Pharmacol Toxicol. https://doi.org/10.1111/bcpt.13648

    Article  Google Scholar 

  71. Taeb S, Ashrafizadeh M, Zarrabi A, Rezapoor S, Musa AE, Farhood B et al (2022) Role of tumor microenvironment in cancer stem cells resistance to radiotherapy. Curr Cancer Drug Targets 22(1):18–30. https://doi.org/10.2174/1568009622666211224154952

    Article  CAS  Google Scholar 

  72. Chen Y-H, Yang S-F, Yang C-K, Tsai H-D, Chen T-H, Chou M-C et al (2021) Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep 23(1):88. https://doi.org/10.3892/mmr.2020.11725

    Article  CAS  Google Scholar 

  73. Xia C, Liu C, He Z, Cai Y, Chen J (2020) Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression. J Exp Clin Cancer Res 39(1):127. https://doi.org/10.1186/s13046-020-01627-6

    Article  CAS  Google Scholar 

  74. Li Z, Wang L, Luo N, Zhao Y, Li J, Chen Q et al (2018) Metformin inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the phosphorylation of Akt. Oncol Lett 15(5):7948–7954. https://doi.org/10.3892/ol.2018.8297

    Article  CAS  Google Scholar 

  75. Okumura N, Yoshida H, Kitagishi Y, Nishimura Y, Matsuda S (2011) Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer. Biochem Biophys Res Commun 413(3):395–399

    Article  CAS  Google Scholar 

  76. Li C, Liu VWS, Chan DW, Yao KM, Ngan HYS (2012) LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. Int J Gynecol Cancer 22(1):15

    Article  Google Scholar 

  77. Malki A, Youssef A (2011) Antidiabetic drug metformin induces apoptosis in human MCF breast cancer via targeting ERK signaling. Oncol Res 19(6):275–285. https://doi.org/10.3727/096504011x13021877989838

    Article  Google Scholar 

  78. Zheng L, Yang W, Wu F, Wang C, Yu L, Tang L et al (2013) Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res 19(19):5372–5380

    Article  CAS  Google Scholar 

  79. Lu C-C, Chiang J-H, Tsai F-J, Hsu Y-M, Juan Y-N, Yang J-S et al (2019) Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J Oncol 54(4):1271–1281. https://doi.org/10.3892/ijo.2019.4704

    Article  CAS  Google Scholar 

  80. Han G, Gong H, Wang Y, Guo S, Liu K (2015) AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther 16(1):77–87. https://doi.org/10.4161/15384047.2014.987021

    Article  CAS  Google Scholar 

  81. Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE (2019) NF-kappaB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol 234(10):17187–17204. https://doi.org/10.1002/jcp.28504

    Article  CAS  Google Scholar 

  82. Besli N, Yenmis G, Tunçdemir M, Yaprak Sarac E, Doğan S, Solakoğlu S et al (2020) Metformin suppresses the proliferation and invasion through NF-kB and MMPs in MCF-7 cell line. Turk J Biochem 45(3):295–304. https://doi.org/10.1515/tjb-2019-0197

    Article  CAS  Google Scholar 

  83. Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L, Athar M (2012) Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol 88(5):1149–1156. https://doi.org/10.1111/j.1751-1097.2012.01165.x

    Article  CAS  Google Scholar 

  84. Zhao X-B, Qin Y, Niu Y-L, Yang J (2018) Matrine inhibits hypoxia/reoxygenation-induced apoptosis of cardiac microvascular endothelial cells in rats via the JAK2/STAT3 signaling pathway. Biomed Pharmacother 106:117–124. https://doi.org/10.1016/j.biopha.2018.06.003

    Article  CAS  Google Scholar 

  85. Chiang C-F, Chao T-T, Su Y-F, Hsu C-C, Chien C-Y, Chiu K-C et al (2017) Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling. Oncotarget 8(13):20706–20718. https://doi.org/10.18632/oncotarget.14982

    Article  Google Scholar 

  86. Ding L, Liang G, Yao Z, Zhang J, Liu R, Chen H et al (2015) Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget 6(34):36441–36455. https://doi.org/10.18632/oncotarget.5541

    Article  Google Scholar 

  87. Mortezaee K, Parwaie W, Motevaseli E, Mirtavoos-Mahyari H, Musa AE, Shabeeb D et al (2019) Targets for improving tumor response to radiotherapy. Int Immunopharmacol 76:105847. https://doi.org/10.1016/j.intimp.2019.105847

    Article  CAS  Google Scholar 

  88. Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE et al (2012) Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle 11(2):367–376. https://doi.org/10.4161/cc.11.2.18813

    Article  CAS  Google Scholar 

  89. Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W et al (2014) Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis 5(2):e1088. https://doi.org/10.1038/cddis.2014.59

    Article  CAS  Google Scholar 

  90. Raza MH, Siraj S, Arshad A, Waheed U, Aldakheel F, Alduraywish S et al (2017) ROS-modulated therapeutic approaches in cancer treatment. J Cancer Res Clin Oncol 143(9):1789–1809

    Article  CAS  Google Scholar 

  91. Warkad MS, Kim CH, Kang BG, Park SH, Jung JS, Feng JH et al (2021) Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells. Sci Rep 11(1):14002. https://doi.org/10.1038/s41598-021-93270-0

    Article  CAS  Google Scholar 

  92. Eisenberg-Lerner A, Bialik S, Simon H-U, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16(7):966–975

    Article  CAS  Google Scholar 

  93. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK (2018) Targeting autophagy in cancer. Cancer 124(16):3307–3318

    Article  Google Scholar 

  94. De Santi M, Baldelli G, Diotallevi A, Galluzzi L, Schiavano GF, Brandi G (2019) Metformin prevents cell tumorigenesis through autophagy-related cell death. Sci Rep 9(1):66. https://doi.org/10.1038/s41598-018-37247-6

    Article  CAS  Google Scholar 

  95. Zou G, Bai J, Li D, Chen Y (2019) Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells. Exp Ther Med 18(3):2086–2094. https://doi.org/10.3892/etm.2019.7803

    Article  CAS  Google Scholar 

  96. Ponnusamy L, Natarajan SR, Thangaraj K, Manoharan R (2020) Therapeutic aspects of AMPK in breast cancer: progress, challenges, and future directions. Biochim Biophys Acta 1874(1):188379

    CAS  Google Scholar 

  97. Yuan J, Dong X, Yap J, Hu J (2020) The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol 13(1):1–19

    Article  Google Scholar 

  98. Liu S, Yue C, Chen H, Chen Y, Li G (2020) Metformin promotes beclin1-dependent autophagy to inhibit the progression of gastric cancer. Onco Targets Ther 13:4445

    Article  CAS  Google Scholar 

  99. Gao C, Fang L, Zhang H, Zhang W-S, Li X-O, Du S-Y (2020) Metformin induces autophagy via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma cells. Cancer Manage Res 12:5803

    Article  CAS  Google Scholar 

  100. Wang Y, Xu W, Yan Z, Zhao W, Mi J, Li J et al (2018) Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res 37(1):63. https://doi.org/10.1186/s13046-018-0731-5

    Article  CAS  Google Scholar 

  101. Sui X, Xu Y, Yang J, Fang Y, Lou H, Han W et al (2014) Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS ONE 9(5):e97781. https://doi.org/10.1371/journal.pone.0097781

    Article  CAS  Google Scholar 

  102. Guo L, Cui J, Wang H, Medina R, Zhang S, Zhang X et al (2021) Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways. Mol Ther 20:119–131. https://doi.org/10.1016/j.omto.2020.11.004

    Article  CAS  Google Scholar 

  103. Vial G, Detaille D, Guigas B (2019) Role of mitochondria in the mechanism (s) of action of metformin. Front Endocrinol (Lausanne) 10:294

    Article  Google Scholar 

  104. Li B, Zhou P, Xu K, Chen T, Jiao J, Wei H et al (2020) Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci 16(1):74–84. https://doi.org/10.7150/ijbs.33787

    Article  CAS  Google Scholar 

  105. Choi KS (2012) Autophagy and cancer. Exp Mol Med 44(2):109–120

    Article  CAS  Google Scholar 

  106. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7(12):961–967

    Article  CAS  Google Scholar 

  107. Saladini S, Aventaggiato M, Barreca F, Morgante E, Sansone L, Russo MA et al (2019) Metformin impairs glutamine metabolism and autophagy in tumour cells. Cells 8(1):49

    Article  CAS  Google Scholar 

  108. Tan M, Wu A, Liao N, Liu M, Guo Q, Yi J et al (2018) Inhibiting ROS-TFE3-dependent autophagy enhances the therapeutic response to metformin in breast cancer. Free Radic Res 52(8):872–886. https://doi.org/10.1080/10715762.2018.1485075

    Article  CAS  Google Scholar 

  109. Acosta JC, Gil J (2012) Senescence: a new weapon for cancer therapy. Trends Cell Biol 22(4):211–219

    Article  CAS  Google Scholar 

  110. Zeng S, Shen WH, Liu L (2018) Senescence and cancer. Cancer Transl Med 4(3):70–74. https://doi.org/10.4103/ctm.ctm_22_18

    Article  CAS  Google Scholar 

  111. Lau L, Porciuncula A, Yu A, Iwakura Y, David G (2019) Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role. Mol Cell Biol. https://doi.org/10.1128/mcb.00586-18

    Article  Google Scholar 

  112. Ortiz-Montero P, Londoño-Vallejo A, Vernot J-P (2017) Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun Signal 15(1):17. https://doi.org/10.1186/s12964-017-0172-3

    Article  CAS  Google Scholar 

  113. Menendez JA, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Vellon L et al (2011) Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer. Aging 3(11):1063–1077. https://doi.org/10.18632/aging.100407

    Article  CAS  Google Scholar 

  114. Williams CC, Singleton BA, Llopis SD, Skripnikova EV (2013) Metformin induces a senescence-associated gene signature in breast cancer cells. J Health Care Poor Underserved 24(1 Suppl):93–103. https://doi.org/10.1353/hpu.2013.0044

    Article  Google Scholar 

  115. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Quirantes R, Segura-Carretero A, Micol V et al (2012) Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205. Cell Cycle 11(6):1235–1246. https://doi.org/10.4161/cc.11.6.19665

    Article  CAS  Google Scholar 

  116. Deschênes-Simard X, Parisotto M, Rowell MC, Le Calvé B, Igelmann S, Moineau-Vallée K et al (2019) Circumventing senescence is associated with stem cell properties and metformin sensitivity. Aging Cell 18(2):e12889

    Article  Google Scholar 

  117. Yi G, He Z, Zhou X, Xian L, Yuan T, Jia X et al (2013) Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol 43(5):1503–1510. https://doi.org/10.3892/ijo.2013.2077

    Article  CAS  Google Scholar 

  118. Li P, Zhao M, Parris AB, Feng X, Yang X (2015) p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochem Biophys Res Commun 464(4):1267–1274. https://doi.org/10.1016/j.bbrc.2015.07.117

    Article  CAS  Google Scholar 

  119. Skinner HD, Sandulache VC, Ow TJ, Meyn RE, Yordy JS, Beadle BM et al (2012) TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res 18(1):290–300

    Article  CAS  Google Scholar 

  120. Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE et al (2013) Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κ B activation. Aging Cell 12(3):489–498

    Article  CAS  Google Scholar 

  121. Jiang M, Qiao M, Zhao C, Deng J, Li X, Zhou C (2020) Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res 9(4):1569–1584

    Article  CAS  Google Scholar 

  122. Bebber CM, Müller F, Prieto Clemente L, Weber J, von Karstedt S (2020) Ferroptosis in cancer cell biology. Cancers (Basel) 12(1):164. https://doi.org/10.3390/cancers12010164

    Article  CAS  Google Scholar 

  123. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK et al (2019) CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569(7755):270–274

    Article  CAS  Google Scholar 

  124. Yang J, Zhou Y, Xie S, Wang J, Li Z, Chen L et al (2021) Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res 40(1):206. https://doi.org/10.1186/s13046-021-02012-7

    Article  CAS  Google Scholar 

  125. Banerjee S, Kumar M, Wiener R (2020) Decrypting UFMylation: how proteins are modified with UFM1. Biomolecules 10(10):1442

    Article  CAS  Google Scholar 

  126. Hou Y, Cai S, Yu S, Lin H (2021) Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer. Acta Biochim Biophys Sin (Shanghai) 53(3):333–341. https://doi.org/10.1093/abbs/gmaa180

    Article  CAS  Google Scholar 

  127. Gong Y, Fan Z, Luo G, Yang C, Huang Q, Fan K et al (2019) The role of necroptosis in cancer biology and therapy. Mol Cancer 18(1):100. https://doi.org/10.1186/s12943-019-1029-8

    Article  Google Scholar 

  128. O’Reilly E, Tirincsi A, Logue SE, Szegezdi E (2016) The Janus face of death receptor signaling during tumor immunoediting. Front Immunol. https://doi.org/10.3389/fimmu.2016.00446

    Article  Google Scholar 

  129. Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38(2):209–223. https://doi.org/10.1016/j.immuni.2013.02.003

    Article  CAS  Google Scholar 

  130. Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Najafi M (2020) Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol 86:106761. https://doi.org/10.1016/j.intimp.2020.106761

    Article  CAS  Google Scholar 

  131. Dias Lopes NM, Marinello PC, Sanches LJ, da Silva Brito WA, Lovo-Martins MI, Pinge-Filho P et al (2020) Patterns of cell death induced by metformin in human MCF-7 breast cancer cells. Pathology 216(11):153199. https://doi.org/10.1016/j.prp.2020.153199

    Article  CAS  Google Scholar 

  132. Babcook MA, Sramkoski RM, Fujioka H, Daneshgari F, Almasan A, Shukla S et al (2014) Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4–2B osseous metastatic castration-resistant prostate cancer cells. Cell Death Dis 5(11):e1536-e. https://doi.org/10.1038/cddis.2014.500

    Article  CAS  Google Scholar 

  133. Lee SB, Kim JJ, Han SA, Fan Y, Guo LS, Aziz K et al (2019) The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome. Nat Cell Biol 21(8):940–951. https://doi.org/10.1038/s41556-019-0356-8

    Article  CAS  Google Scholar 

  134. Fang Y, Tian S, Pan Y, Li W, Wang Q, Tang Y et al (2020) Pyroptosis: a new frontier in cancer. Biomed Pharmacother 121:109595. https://doi.org/10.1016/j.biopha.2019.109595

    Article  CAS  Google Scholar 

  135. Tan Y, Chen Q, Li X, Zeng Z, Xiong W, Li G et al (2021) Pyroptosis: a new paradigm of cell death for fighting against cancer. J Exp Clin Cancer Res 40(1):153. https://doi.org/10.1186/s13046-021-01959-x

    Article  CAS  Google Scholar 

  136. Xia X, Wang X, Cheng Z, Qin W, Lei L, Jiang J et al (2019) The role of pyroptosis in cancer: pro-cancer or pro-“host”? Cell Death Dis 10(9):650. https://doi.org/10.1038/s41419-019-1883-8

    Article  CAS  Google Scholar 

  137. Wang L, Li K, Lin X, Yao Z, Wang S, Xiong X et al (2019) Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis. Cancer Lett 450:22–31. https://doi.org/10.1016/j.canlet.2019.02.014

    Article  CAS  Google Scholar 

  138. Zheng Z, Bian Y, Zhang Y, Ren G, Li G (2020) Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle 19(10):1089–1104. https://doi.org/10.1080/15384101.2020.1743911

    Article  CAS  Google Scholar 

  139. Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272(2):177–185

    Article  CAS  Google Scholar 

  140. Gilmore AP (2005) Anoikis. Cell Death Differ 12(2):1473–1477. https://doi.org/10.1038/sj.cdd.4401723

    Article  CAS  Google Scholar 

  141. Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A et al (2012) Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer 19(3):447–456. https://doi.org/10.1530/erc-12-0046

    Article  CAS  Google Scholar 

  142. An T, Zhang Z, Li Y, Yi J, Zhang W, Chen D et al (2019) Integrin β1-mediated cell–cell adhesion augments metformin-induced anoikis. Int J Mol Sci 20(5):1161. https://doi.org/10.3390/ijms20051161

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Foundation of China (82174466 to WXY), six “1” Project of Jiangsu Province (LGY2016012 to WXY), Social Development Project of Jiangsu Province (BE2019768 to WXY). The funding institutions did not have any roles in the study design, data collection, or analysis.

Author information

Author notes

  1. These authors have same contribution in this paper.

Authors and Affiliations

  1. Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China

    Xiao-yu Wu, Xiang-kun Huan & Guan-nan Wu

  2. Department of Gynaecology, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China

    Wen-Wen Xu

  3. Department of General Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Gang Li

  4. Digestive Endoscopy Center, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China

    Yu-Hong Zhou

  5. Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Masoud Najafi

Authors
  1. Xiao-yu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen-Wen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiang-kun Huan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guan-nan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Hong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masoud Najafi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XW, WX, XH, GW, GL, and YZ were involved in the preparing first draft. GL and MN edited the manuscript for scientific contents and language.

Corresponding authors

Correspondence to Gang Li, Yu-Hong Zhou or Masoud Najafi.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This article does not contain human or animal studies performed by any of the authors.

Informed consent

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Xy., Xu, WW., Huan, Xk. et al. Mechanisms of cancer cell killing by metformin: a review on different cell death pathways. Mol Cell Biochem 478, 197–214 (2023). https://doi.org/10.1007/s11010-022-04502-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04502-4

Keywords

Search

Navigation