Application of ferroptosis strategy to overcome tumor therapy resistance in breast and different cancer cells

Document Type : Review Article


1 Department of General Surgery Sub Specialty Breast Surgery, Shanxi First Medical Hospital affiliated to Shanxi Medical University, Yingze District, 030000, Taiyuan, China

2 Department of Pharmacology, Bahauddin Zakriya University Multan, Pakistan

3 Primary & Secondary Healthcare Department, Govt. of Punjab, Pakistan

4 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China



This literature review emphasizes the innovative role of ferroptosis in cancer treatment. Ferroptosis is a kind of deliberate cell death that is characterized by the generation of lipid peroxides and needs the presence of iron. Ferroptosis is a controlled cell death process that adheres to certain rules and regulations. The inhibition of System Xc- and the involvement of GPX4 are two of the primary areas of exploration that are engaged in the process of ferroptosis. This review explores the treatments that are used to treat ferroptosis in a range of malignancies, with a particular focus on breast carcinoma. Attention is paid to certain pathways, such as the FSP1-independent regulation of glutathione, involvement of cholesterol, and the prominin 2-MVB/exosome-ferritin pathway. Ferroptosis plays a key role in resistance to tumor therapy.


Main Subjects

1. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res 2021; 31: 107-125.
2. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: Past, present and future. Cell Death Dis 2020;11:88-100. 
3. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 2009; 16: 3-11. 
4. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003; 3: 285-296. 
5. Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 2022; 82: 2215-2227. 
6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060-1072. 
7. Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 2019; 23: 4900-4912.
8. Rishi G, Huang G, Subramaniam VN. Cancer: The role of iron and ferroptosis. Int J Biochem Cell Biol 2021; 141: 106094.
9. Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci 2016; 73: 2195-2209.
10. Nie J, Lin B, Zhou M, Wu L, Zheng T. Role of ferroptosis in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2018; 144: 2329-2337.
11. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017; 547: 453-457.
12. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun 2019; 10: 1617-1629.
13. Wang Y, Sun S, Zhang Z, Shi D. Nanomaterials for cancer precision medicine. Adv Mater 2018; 30: e1705660. 
14. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 2019; 569: 270-274. 
15. Zhao Y, Li Y, Zhang R, Wang F, Wang T, Jiao Y. The role of erastin in ferroptosis and its prospects in cancer therapy. Onco Targets Ther 2020; 13: 5429-5441.
16. Bartolacci C, Andreani C, El-Gammal Y, Scaglioni PP. Lipid metabolism regulates oxidative stress and ferroptosis in RAS-driven cancers: A perspective on cancer progression and therapy. Front Mol Biosci 2021; 8: 706650-706668.
17. Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol 2020; 66: 89-100.
18. Hu Q, Zhang Y, Lou H, Ou Z, Liu J, Duan W, et al. GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis 2021; 12: 706-714.
19. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014; 10: 9-17.
20. Jenkins NL, James SA, Salim A, Sumardy F, Speed TP, Conrad M, et al. Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans. Elife 2020; 9: e56580-56607.
21. Stockwell BR, Jiang X, Gu W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol 2020; 30: 478-490.
22. Frazer DM, Anderson GJ. The regulation of iron transport. Biofactors 2014; 40: 206-214.
23. Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol 2007; 69: 69-85.
24. Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater 2019; 31: e1904197.
25. Venkataramani V. Iron homeostasis and metabolism: Two sides of a coin. Adv Exp Med Biol. 2021; 1301: 25-40.
26. Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: New players in metabolism, cell death, and disease. Trends Biochem Sci 2016; 41: 274-286.
27. Chen Y, Liu S, Li J, Li Z, Quan J, Liu X, et al. The latest view on the mechanism of ferroptosis and its research progress in spinal cord injury. Oxid Med Cell Longev 2020; 2020: 6375938-6375948.
28. Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting ferroptosis to iron out cancer. Cancer Cell 2019; 35: 830-849.
29. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 2015; 59: 298-308.
30. Kwon MY, Park E, Lee SJ, Chung SW. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget 2015; 6: 24393-24403.
31. Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 2015; 34: 5617-5625.
32. Dias C, Nylandsted J. Plasma membrane integrity in health and disease: Significance and therapeutic potential. Cell Discov 2021; 7: 4-21.
33. Qu C, Peng Y, Liu S. Ferroptosis biology and implication in cancers. Front Mol Biosci 2022; 9: 892957-892967.
34. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: Molecular mechanisms and health implications. Cell Res 2021;31:107-125.
35. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol 2020; 21: 85-100.
36. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell 2019; 73: 354-363.
37. Skonieczna M, Cieslar-Pobuda A, Saenko Y, Foksinski M, Olinski R, Rzeszowska-Wolny J, et al. The Impact of DIDS-induced inhibition of voltage-dependent anion channels (VDAC) on cellular response of lymphoblastoid cells to ionizing radiation. Med Chem 2017; 13: 477-483.
38. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864-868.
39. Zhang X, Xing X, Liu H, Feng J, Tian M, Chang S, et al. Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow. Int J Radiat Biol 2020; 96: 584-595.
40. Kapralov AA, Yang Q, Dar HH, Tyurina YY, Anthonymuthu TS, Kim R, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 2020; 16: 278-290. 
41. Wang H, Liu C, Zhao Y, Gao G. Mitochondria regulation in ferroptosis. Eur J Cell Biol 2020; 99: 151058. 
42. Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020; 368: 85-89.
43. Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy 2021;17: 2054-2081. 
44. Jiang L, Hickman JH, Wang SJ, Gu W. Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle 2015; 14: 2881-2885.
45. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520: 57-62.
46. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22: 266-282.
47. Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta 2013; 1830: 3289-3303.
48. Forcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics 2019; 19: e1800311.
49. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15: 234-245.
50. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317-331.
51. Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22: 266-282.
52. Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigó R, et al. Characterization of mammalian selenoproteomes. Science 2003; 300: 1439-1443.
53. Warner GJ, Berry MJ, Moustafa ME, Carlson BA, Hatfield DL, Faust JR. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine. J Biol Chem 2000; 275: 28110-28119.
54. Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: A novel anti-tumor action for cisplatin. Cancer Res Treat 2018; 50: 445-460.
55. Rees MG, Seashore-Ludlow B, Cheah JH, Adams DJ, Price EV, Gill S, et al. Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat Chem Biol 2016; 12: 109-116.
56. Sleire L, Skeie BS, Netland IA, Førde HE, Dodoo E, Selheim F, et al. Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion. Oncogene 2015; 34: 5951-5959.
57. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 2014; 3: e02523-2547.
58. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 2016; 12: 497-503.
59. Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015; 2: 517-532.
60. Weïwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 2012; 22:1822-1826.
61. Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO(2) initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018; 14: 507-515.
62. Basit F, van Oppen LM, Schöckel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC, et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis 2017; 8: e2716-2726.
63. Ma S, Dielschneider RF, Henson ES, Xiao W, Choquette TR, Blankstein AR, et al. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS One 2017; 12: e0182921-182934.
64. Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 2017; 20: 1692-1704.
65. Torti SV, Torti FM. Iron: The cancer connection. Mol Aspects Med 2020; 75: 100860.
66. Brown RAM, Richardson KL, Kabir TD, Trinder D, Ganss R, Leedman PJ. Altered iron metabolism and impact in cancer biology, metastasis, and immunology. Front Oncol 2020; 10: 476-500.
67. Ma S, Henson ES, Chen Y, Gibson SB. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis 2016; 7: e2307-2317.
68. Greenshields AL, Shepherd TG, Hoskin DW. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog 2017; 56: 75-93.
69. Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G, et al. Iron addiction: A novel therapeutic target in ovarian cancer. Oncogene 2017; 36: 4089-4099.
70. Buccarelli M, Marconi M, Pacioni S, De Pascalis I, D’Alessandris QG, Martini M, et al. Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. Cell Death Dis 2018; 9: 841-857.
71. Probst L, Dächert J, Schenk B, Fulda S. Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. Biochem Pharmacol 2017; 140: 41-52.    
72. Sun X, Niu X, Chen R, He W, Chen D, Kang R, Tang D. Metallothioneinā€1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 2016; 64: 488-500. 
73. Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol 2015; 2: e1054549-1054555.
74. Schott C, Graab U, Cuvelier N, Hahn H, Fulda S. Oncogenic RAS mutants confer resistance of RMS13 rhabdomyosarcoma cells to oxidative stress-induced ferroptotic cell death. Front Oncol 2015; 5: 131-137.
75. Chen MS, Wang SF, Hsu CY, Yin PH, Yeh TS, Lee HC, et al. CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway. Oncotarget 2017; 8: 114588-114602.
76. Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, et al. Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget 2016; 7: 11756-11769.
77. Wu ZH, Tang Y, Yu H, Li HD. The role of ferroptosis in breast cancer patients: a comprehensive analysis. Cell Death Discov 2021; 7: 93-102.
78. Han C, Liu Y, Dai R, Ismail N, Su W, Li B. Ferroptosis and its potential role in human diseases. Front Pharmacol 2020; 11: 239-257.
79. Ji H, Wang W, Li X, Han X, Zhang X, Wang J, et al. p53: A double-edged sword in tumor ferroptosis. Pharmacol Res 2022; 177: 106013.
80. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019; 575: 693-698.
81. Xu H, Zhou S, Tang Q, Xia H, Bi F. Cholesterol metabolism: New functions and therapeutic approaches in cancer. Biochim Biophys Acta Rev Cancer 2020; 1874: 188394.
E, Yang S, Taxter T, et al. Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis. J Biol Chem 2021; 296: 100100-100112.
83. Liu W, Chakraborty B, Safi R, Kazmin D, Chang CY, McDonnell DP. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nat Commun 2021; 12: 5103-5117.
84. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol 2021;18: 280-296.
85. Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell 2019; 51: 575-586.
86. Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: A current overview. Clin Exp Metastasis 2018; 35: 309-318.
awson MA. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer 2020; 20: 743-756.
88. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-627.
89. Bukowski K, Kciuk M, Kontek R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int J Mol Sci 2020; 21: 3233-3256.
90. Bax BD, Murshudov G, Maxwell A, Germe T. DNA topoisomerase inhibitors: Trapping a DNA-cleaving machine in motion. J Mol Biol 2019; 431: 3427-3449.
91. Tang Z, Dong H, Li T, Wang N, Wei X, Wu H, et al. The synergistic reducing drug resistance effect of cisplatin and ursolic acid on osteosarcoma through a multistep mechanism involving ferritinophagy. Oxid Med Cell Longev 2021; 2021: 5192271-5192287.
92. Han L, Li L, Wu G. Induction of ferroptosis by carnosic acid-mediated inactivation of Nrf2/HO-1 potentiates cisplatin responsiveness in OSCC cells. Mol Cell Probes 2022; 64: 101821.
93. Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol 2020; 16: 302-309.
94. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res 2016; 26: 1021-1032.
95. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 2022; 22: 381-396.
96. Yan Wenqi, Wei Lingxi, Arshad Mehmood, Wahid Shah. Nanotechnology-enabled therapies improve blood-brain barrier challenges in brain tumor. Int J Polymeric Materials and Polymeric Biomater 2023; 12: 1-22. 
97. Murad Khan, Suleman Shah, Wahid Shah, Ikram Khan, Hamid Ali, Ijaz Ali, et al. International Rev Immunol 2024; 2: 1-9.