International Journal of Biomedical Science and Engineering

Submit a Manuscript

Publishing with us to make your research visible to the widest possible audience.

Propose a Special Issue

Building a community of authors and readers to discuss the latest research and develop new ideas.

Research Article |

The Developments and Advancements in Ferroptosis Research for the Treatment of Pancreatic Cancer: A Review

Pancreatic cancer (PC) is a highly lethal form of cancer that presents significant challenges for early detection. It rapidly metastasizes and often shows resistance to conventional chemotherapy. Consequently, the prognosis for most patients is bleak. Despite substantial advances in medical research, the number of viable treatment options remains limited, highlighting the urgent need for innovative strategies to improve patient outcomes. Ferroptosis is a unique type of cell death triggered by excessive iron levels. It sets itself apart from other forms of cell death, such as apoptosis and necrosis, characterized by an overabundance of lipid peroxides and reactive oxygen species. Ferroptosis plays a critical role in sustaining the viability of healthy cells and tissues. However, specific cancerous cells are vulnerable to this process. The resistance of pancreatic cancer cells to chemotherapeutic drugs has become the main reason for chemotherapy failure. Inducing ferroptosis in cancer cells is the best way to overcome chemotherapy resistance. Small molecule drugs can cause iron death through glutathione depletion and lipid peroxidation. Ferroptosis inhibitors may become an adjuvant therapy enhancer, acting with ferroptosis inducers on pancreatic tumor cells. As such, the induction of ferroptosis may offer a promising new avenue for cancer treatment. This article examines PC's iron-induced cell death regulatory mechanism and potential therapeutic applications.

Ferroptosis, Pancreatic Cancer (PC), Glutathione Peroxidase 4 (GPX4), System XC, Tumor Microenvironment (TME)

APA Style

Zhang, J., Zhao, Y. (2023). The Developments and Advancements in Ferroptosis Research for the Treatment of Pancreatic Cancer: A Review. International Journal of Biomedical Science and Engineering, 11(4), 54-60. https://doi.org/10.11648/j.ijbse.20231104.12

ACS Style

Zhang, J.; Zhao, Y. The Developments and Advancements in Ferroptosis Research for the Treatment of Pancreatic Cancer: A Review. Int. J. Biomed. Sci. Eng. 2023, 11(4), 54-60. doi: 10.11648/j.ijbse.20231104.12

AMA Style

Zhang J, Zhao Y. The Developments and Advancements in Ferroptosis Research for the Treatment of Pancreatic Cancer: A Review. Int J Biomed Sci Eng. 2023;11(4):54-60. doi: 10.11648/j.ijbse.20231104.12

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Seiler A, Schneider M, Forster H, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent-and AIF-mediated cell death. Cell Metab. 2008; 8 (3): 237-248.
2. Moloney JN, Cotter TG. ROS signaling in the biology of cancer. Semin Cell Dev Biol. 2018; 80: 50-64.
3. Zhang J, Wang X, Vikash V, et al. ROS and ROS-mediated cellular signaling. Oxid Med Cell Longev. 2016; 2016: 4350965.
4. He J, Yang X, Men B, Wang D. Interfacial mechanisms of heterogeneous fenton reactions catalyzed by iron-based materials: a review. J Environ Sci (China). 2016; 39: 97-109.
5. Santini SJ, Cordone V, Falone S, et al. Role of mitochondria in the oxidative stress induced by electromagnetic fifields: focus on reproductive systems. Oxid Med Cell Longev. 2018; 2018: 5076271.
6. Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat ChemBiol. 2019; 15 (12): 1137-1147.
7. ImaiH, MatsuokaM, KumagaiT, SakamotoT, KoumuraT. Lipidperoxidation-dependent cell death regulated by GPX4 and ferroptosis. Curr Top Microbiol Immunol. 2017; 403: 143-170.
8. Lin CH, Lin PP, Lin CY, et al. Decreased mRNA expression for the two subunits of system xc (-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. J Psychiatr Res. 2016; 72: 58-63.
9. Koppula P, Zhang Y, Zhuang L, Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond). 2018; 38 (1): 12.
10. Ruiu R, Rolih V, Bolli E, et al. Fighting breast cancer stem cells through the immune-targeting of the xCT cystine-glutamate antiporter. Cancer Immunol Immunother. 2019; 68 (1): 131-141.
11. Paul BD, Sbodio JI, Snyder SH. Cysteine metabolism in neuronal redox homeostasis. Trends Pharmacol Sci. 2018; 39 (5): 513-524.
12. Ekoue DN, He C, Diamond AM, Bonini MG. Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which driveoncogenesis. Biochim Biophys Acta Bioenerg. 2017; 1858: 628-632.
13. Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016; 73 (11-12): 2195-2209.
14. Anbarasan T, Bourdon JC. The emerging landscape of p53 isoforms in physiology, cancer and degenerative diseases. Int J Mol Sci. 2019; 20 (24).
15. Pitolli C, Wang Y, Candi E, Shi Y, Melino G, Amelio I. p53-mediated tumor suppression: DNA-damage response and alternative mechanisms. Cancers (Basel). 2019; 11 (12): 1983.
16. Saint-Germain E, Mignacca L, Vernier M, Bobbala D, Ilangumaran S, Ferbeyre G. SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes. Aging (Albany NY). 2017; 9 (10): 2137-2162.
17. Wang SJ, Li D, Ou Y, et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep. 2016; 17 (2): 366-373.
18. Gupta AK, Bharadwaj M, Kumar A, Mehrotra R. Spiro-oxindoles as a promising class of small molecule inhibitors of p53-MDM2 interaction useful in targeted cancer therapy. Top Curr Chem (Cham). 2017; 375 (1): 3.
19. Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520 (7545): 57-62.
20. Jiang L, Hickman JH, Wang SJ, Gu W. Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle. 2015; 14 (18): 2881-2885.
21. Zhang W, Gai C, Ding D, Wang F, Li W. Targeted p53 on small-molecules-induced ferroptosis in cancers. Front Oncol. 2018; 8: 507.
22. Kang R, Kroemer G, Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 2019; 133: 162-168.
23. Ou Y, Wang SJ, Li D, Chu B, Gu W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci USA. 2016; 113 (44): E6806-E6812.
24. Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019; 575 (7784): 693-698.
25. Liu Z, Dong W, Yang B, et al. Tetrachlorobenzoquinone-induced Nrf2 confers neuron-like PC12 cells resistance to endoplasmic reticulum stress via regulating glutathione synthesis and protein thiol homeostasis. Chem Res Toxicol. 2018; 31 (11): 1230-1239.
26. Fan Z, Wirth AK, Chen D, et al. Nrf2-keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017; 6: 371.
27. Sun X, Ou Z, Chen R, et al. Activation of the p62-keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016; 63 (1): 173-184.
28. Chiang S-K, Chen S-E, Chang L-C. A dual role of hemeoxygenase-1 in cancer cells. Int J Mol Sci. 2018; 20 (1): 39.
29. Jonckheere, N., Vasseur, R., Van Seuningen, I., 2017. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: from cell signaling network, target genes, biological processes to therapeutic targeting. Crit. Rev. Oncol. Hematol. 111, 7-19.
30. Thomas, D., Radhakrishnan, P., 2019. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol. Cancer 18 (1), 14.
31. Haqq, J., Howells, L. M., Garcea, G., Metcalfe, M. S., Steward, W. P., Dennison, A. R., 2014. Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur. J. Cancer 50 (15), 2570-2582.
32. Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., Asara, J. M., Evans, R. M., Cantley, L. C., Lyssiotis, C. A., Kimmelman, A. C., 2016. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536 (7617), 479-483.
33. Endo, S., Nakata, K., Ohuchida, K., Takesue, S., Nakayama, H., Abe, T., Koikawa, K., Okumura, T., Sada, M., Horioka, K., Zheng, B., Mizuuchi, Y., Iwamoto, C., Murata, M., Moriyama, T., Miyasaka, Y., Ohtsuka, T., Mizumoto, K., Oda, Y., Hashizume, M., Nakamura, M., 2017. Autophagy is required for activation of pancreatic stellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. Gastroenterology 152 (6), 1492-1506 e24.
34. Parker, S. J., Amendola, C. R., Hollinshead, K. E. R., Yu, Q., Yamamoto, K., Encarnaci´on-Rosado, J., Rose, R. E., LaRue, M. M., Sohn, A. S. W., Biancur, D. E., Paulo, J. A., Gygi, S. P., Jones, D. R., Wang, H., Philips, M. R., Bar-Sagi, D., Mancias, J. D., Kimmelman, A. C., 2020. Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer. Cancer Discov. 10 (7), 1018-1037.
35. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J., Lotze, M. T., 2012. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249 (1), 158-175.
36. Orlacchio, A., Mazzone, P., 2021. The role of toll-like receptors (TLRs) mediated inflammation in pancreatic cancer pathophysiology. Int. J. Mol. Sci. 22 (23), 12743.
37. Dai, E., Han, L., Liu, J., Xie, Y., Kroemer, G., Klionsky, D. J., Zeh, H. J., Kang, R., Wang, J., Tang, D., 2020c. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16 (11), 2069-2083.
38. Dai, E., Meng, L., Kang, R., Wang, X., Tang, D., 2020a. ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem. Biophys. Res. Commun. 522 (2), 415-421.
39. Song, X., Zhu, S., Chen, P., Hou, W., Wen, Q., Liu, J., Xie, Y., Liu, J., Klionsky, D. J., Kroemer, G., Lotze, M. T., Zeh, H. J., Kang, R., Tang, D., 2018. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc-activity. Curr. Biol. 28 (15), 2388-2399 e5.
40. Zhu, S., Zhang, Q., Sun, X., Zeh 3rd, H. J., Lotze, M. T., Kang, R., Tang, D., 2017. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 77 (8), 2064-2077.
41. Badgley, M. A., Kremer, D. M., Maurer, H. C., DelGiorno, K. E., Lee, H. J., Purohit, V., Sagalovskiy, I. R., Ma, A., Kapilian, J., Firl, C. E. M., Decker, A. R., Sastra, S. A., Palermo, C. F., Andrade, L. R., Sajjakulnukit, P., Zhang, L., Tolstyka, Z. P., Hirschhorn, T., Lamb, C., Liu, T., Gu, W., Seeley, E. S., Stone, E., Georgiou, G., Manor, U., Iuga, A., Wahl, G. M., Stockwell, B. R., Lyssiotis, C. A., Olive, K. P., 2020. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368 (6486), 85-89.
42. Hu, N., Bai, L., Dai, E., Han, L., Kang, R., Li, H., Tang, D., 2021. Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis. Biochem. Biophys. Res. Commun. 536, 100-106.
43. Gao, H., Bai, Y., Jia, Y., Zhao, Y., Kang, R., Tang, D., Dai, E., 2018. Ferroptosis is a lysosomal cell death process. Biochem. Biophys. Res. Commun. 503 (3), 1550-1556.
44. Song, X., Liu, J., Kuang, F., Chen, X., Zeh 3rd, H. J., Kang, R., Kroemer, G., Xie, Y., Tang, D., 202 1. PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep. 34 (8), 108767.
45. Kremer, D. M., Nelson, B. S., Lin, L., Yarosz, E. L., Halbrook, C. J., Kerk, S. A., Sajjakulnukit, P., Myers, A., Thurston, G., Hou, S. W., Carpenter, E. S., Andren, A. C., Nwosu, Z. C., Cusmano, N., Wisner, S., Mbah, N. E., Shan, M., Das, N. K., Magnuson, B., Little, A. C., Savani, M. R., Ramos, J., Gao, T., Sastra, S. A., Palermo, C. F., Badgley, M. A., Zhang, L., Asara, J. M., McBrayer, S. K., di Magliano, M. P., Crawford, H. C., Shah, Y. M., Olive, K. P., Lyssiotis, C. A., 2021. GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. Nat. Commun. 12 (1), 4860.
46. Dai, E., Han, L., Liu, J., Xie, Y., Zeh, H. J., Kang, R., Bai, L., Tang, D., 2020b. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat. Commun. 11 (1), 6339.
47. Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., Matrisian, L. M., 20 1 4. Projecting cancer incidence and deaths to 20 3 0: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74 (11), 2913-2921.
48. Mizrahi, J. D., Surana, R., Valle, J. W., Shroff, R. T., 2020. Pancreatic cancer. Lancet 395 (10242), 2008-2020.
49. Brunner, M., Wu, Z., Krautz, C., Pilarsky, C., Grützmann, R., Weber, G. F., 2019. Current clinical strategies of pancreatic cancer treatment and open molecular questions. Int. J. Mol. Sci. 20 (18), 4543.
50. Neoptolemos, J. P., Kleeff, J., Michl, P., Costello, E., Greenhalf, W., Palmer, D. H., 2018. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 15 (6), 333-348.
51. Strobel, O., Neoptolemos, J., Jager, D., Buchler, M. W., 2019. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 16 (1), 11-26.
52. Chandana, S., Babiker, H. M., Mahadevan, D., 2019. Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC). Expert Opin. Invest. Drugs 28 (2), 161-177.
53. Bear, A. S., Vonderheide, R. H., O’Hara, M. H., 2020. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell 38 (6), 788-802.
54. Morrison, A. H., Byrne, K. T., Vonderheide, R. H., 2018. Immunotherapy and prevention of pancreatic cancer. Trends Cancer 4 (6), 418-428.
55. Schizas, D., Charalampakis, N., Kole, C., Economopoulou, P., Koustas, E., Gkotsis, E., Ziogas, D., Psyrri, A., Karamouzis, M. V., 2020. Immunotherapy for pancreatic cancer: A 2020 update. Cancer Treat. Rev. 86, 102016.
56. Hosein, A. N., Brekken, R. A., Maitra, A., 2020. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat. Rev. Gastroenterol. Hepatol. 17 (8), 487-505.
57. Hessmann, E., Buchholz, S. M., Demir, I. E., Singh, S. K., Gress, T. M., Ellenrieder, V., Neesse, A., 2020. Microenvironmental determinants of pancreatic cancer. Physiol. Rev. 100 (4), 1707-1751.
58. Ho, W. J., Jaffee, E. M., Zheng, L., 2020. The tumour microenvironment in pancreatic cancer-clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17 (9), 527-540.
59. Hassannia, B., Vandenabeele, P., Vanden, Berghe, T., 2019. Targeting ferroptosis to iron out cancer. Cancer Cell 35 (6), 830-849.
60. Nie, Q., Hu, Y., Yu, X., Li, X., Fang, X., 2022. Induction and application of ferroptosis in cancer therapy. Cancer Cell Int. 22 (1), 12.
61. Zhang, C., Liu, X., Jin, S., Chen, Y., Guo, R., 2022. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol. Cancer 21 (1), 47.
62. Yang, B. C., Leung, P. S., 2020. Irisin is a positive regulator for ferroptosis in pancreatic cancer. Mol. Ther. Oncolytics 18, 457-466.
63. Ye, Z., Zhuo, Q., Hu, Q., Xu, X., Liu, M., Zhang, Z., Xu, W., Liu, W., Fan, G., Qin, Y., Yu, X., Ji, S., 2021. FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox Biol. 38, 101807.
64. Wang, K., Zhang, Z., Tsai, H. I., Liu, Y., Gao, J., Wang, M., Song, L., Cao, X., Xu, Z., Chen, H., Gong, A., Wang, D., Cheng, F., Zhu, H., 2021. Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ. 28 (4), 1222-1236.
65. Kuang, F., Liu, J., Xie, Y., Tang, D., Kang, R., 2021. MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem. Biol. 28 (6), 765-775 e5.
66. Yu, X., Zheng, Q., Zhang, M., Zhang, Q., Zhang, S., He, Y., Guo, W., 2021. A prognostic model of pancreatic cancer based on ferroptosis-related genes to determine its immune landscape and underlying mechanisms. Front Cell Dev. Biol. 9, 746696.
67. Ping, H., Jia, X., Ke, H., 2022. A novel ferroptosis-related lncRNAs signature predicts clinical prognosis and is associated with immune landscape in pancreatic cancer. Front. Genet. 13, 786689.
68. Liang, C., Zhang, X., Yang, M., Dong, X., 2019. Recent progress in ferroptosis inducers for cancer therapy. Adv. Mater. 31 (51), e1904197.