The Role of Iron Chelation Therapy in Prostate Cancer

Mesut Akyüz; Elanur Aydın Karataş

doi:10.5281/zenodo.17786796

The Role of Iron Chelation Therapy in Prostate Cancer

Abstract

Prostate cancer remains a significant clinical challenge despite advances in current therapeutic modalities, with its progression to advanced stages closely associated with profound metabolic reprogramming, including disrupted iron homeostasis. Emerging evidence demonstrates that prostate cancer cells exhibit an “iron addiction,” characterized by enhanced expression of iron import proteins and suppression of iron export pathways, thereby fulfilling their elevated proliferative and metabolic requirements. Iron chelation therapy has consequently gained attention as a promising approach to target these iron-dependent processes by limiting intracellular iron availability, leading to the disruption of essential enzymes, signaling pathways, and redox balance. This review summarizes the mechanistic rationale, preclinical findings, and clinical hurdles related to the application of iron chelators in prostate cancer treatment. Furthermore, novel chelating agents and combination strategies are highlighted, with a focus on addressing limitations encountered in early clinical trials. Collectively, current evidence suggests that targeting iron metabolism holds considerable potential as a complementary strategy to enhance the efficacy of conventional therapies in prostate cancer management.

Keywords

Prostate cancer , Iron metabolism , Iron chelation therapy , Metabolic reprogramming

References

1. WHO. Globocan 2022, 2022, International Agency for Research on Cancer: World Health Organization. Accessed 08 May 2025
2. Kontoghiorghes GJ. New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer. International Journal of Molecular Sciences 2022;23.
3. Houédé N, Rébillard X, Bouvet S, Kabani S, Fabbro-Peray P, Trétarre B, et al. Impact on quality of life 3 years after diagnosis of prostate cancer patients below 75 at diagnosis: an observational case-control study. BMC Cancer 2020;20:757.
4. Ankolekar A, Vanneste BGL, Bloemen-van Gurp E, van Roermund JG, van Limbergen EJ, van de Beek K, et al. Development and validation of a patient decision aid for prostate Cancer therapy: from paternalistic towards participative shared decision making. BMC Med Inform Decis Mak 2019;19:130.
5. Dyer A, Kirby M, White ID, Cooper AM. Management of erectile dysfunction after prostate cancer treatment: cross-sectional surveys of the perceptions and experiences of patients and healthcare professionals in the UK. BMJ Open 2019;9:e030856.
6. Emanu JC, Avildsen IK, Nelson CJ. Erectile dysfunction after radical prostatectomy: prevalence, medical treatments, and psychosocial interventions. Curr Opin Support Palliat Care 2016;10:102-7.
7. Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers 2018;4:18016.
8. Chang YC, Lo WJ, Huang YT, Lin CL, Feng CC, Lin HT, et al. Deferasirox has strong anti-leukemia activity but may antagonize theanti-leukemia effect of doxorubicin. Leuk Lymphoma 2017;58:1-12.
9. Chen JB, Zhang M, Zhang XL, Cui Y, Liu PH, Hu J, et al. Glucocorticoid-Inducible Kinase 2 Promotes Bladder Cancer Cell Proliferation, Migration and Invasion by Enhancing β-catenin/c-Myc Signaling Pathway. J Cancer 2018;9:4774-82.
10. Chen Z, Zhang D, Yue F, Zheng M, Kovacevic Z, Richardson DR. The iron chelators Dp44mT and DFO inhibit TGF-β-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1). J Biol Chem 2012;287:17016-28.

11. Ciccarelli C, Di Rocco A, Gravina GL, Mauro A, Festuccia C, Del Fattore A, et al. Disruption of MEK/ERK/c-Myc signaling radiosensitizes prostate cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 2018;144:1685-99.
12. Degirmenci U, Wang M, Hu J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells 2020;9.
13. Ford SJ, Obeidy P, Lovejoy DB, Bedford M, Nichols L, Chadwick C, et al. Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo. Br J Pharmacol 2013;168:1316-28.
14. Akyüz M, Karataş EA. Investigation of the antitumor effects of deferasirox on prostate cancer cells: insights into proliferation, apoptosis, and invasion mechanisms. Mol Biol Rep. 2025;52.
15. Yamasaki T, Terai S, Sakaida I. Deferoxamine for advanced hepatocellular carcinoma. N Engl J Med 2011;365:576-8.
16. Abdelaal G, Veuger S. Reversing oncogenic transformation with iron chelation. Oncotarget 2021;12:106-24.
17. Vela D. Iron Metabolism in Prostate Cancer; From Basic Science to New Therapeutic Strategies. Front Oncol 2018;8:547.
18. Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends Biochem Sci 2016;41:274-86.
19. Bordini J, Morisi F, Elia AR, Santambrogio P, Pagani A, Cucchiara V, et al. Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models. Clin Cancer Res 2020;26:6387-98.
20. Currie C, Bjerknes C, Myklebust TA, Framroze B. Assessing the Potential of Small Peptides for Altering Expression Levels of the Iron-Regulatory Genes FTH1 and TFRC and Enhancing Androgen Receptor Inhibitor Activity in In Vitro Prostate Cancer Models. Int J Mol Sci 2023;24.
21. Deng Z, Manz DH, Torti SV, Torti FM. Effects of Ferroportin-Mediated Iron Depletion in Cells Representative of Different Histological Subtypes of Prostate Cancer. Antioxid Redox Signal 2019;30:1043-61.
22. Leftin A, Zhao HY, Turkekul M, De Stanchina E, Manova K, Koutcher JA. Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. Sci Rep-Uk 2017;7.
23. Simoes RV, Veeraperumal S, Serganova IS, Kruchevsky N, Varshavsky J, Blasberg RG, et al. Inhibition of prostate cancer proliferation by Deferiprone. Nmr in Biomedicine 2017;30.
24. Park KC, Paluncic J, Kovacevic Z, Richardson DR. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. Free Radic Biol Med 2020;157:154-75.
25. Tu LC, Yan X, Hood L, Lin B. Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells. Mol Cell Proteomics 2007;6:575-88.
26. Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, et al. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res 2003;63:1731-6.
27. Dixon KM, Lui GY, Kovacevic Z, Zhang D, Yao M, Chen Z, et al. Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells. Br J Cancer 2013;108:409-19.
28. Sharma A, Mendonca J, Ying J, Kim HS, Verdone JE, Zarif JC, et al. The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion. Mol Oncol 2017;11:655-69.
29. Song Y, Oda Y, Hori M, Kuroiwa K, Ono M, Hosoi F, et al. N-myc downstream regulated gene-1/Cap43 may play an important role in malignant progression of prostate cancer, in its close association with E-cadherin. Hum Pathol 2010;41:214-22.
30. Cheng TL, Symons M, Jou TS. Regulation of anoikis by Cdc42 and Rac1. Exp Cell Res 2004;295:497-511.
31. Wang Y, Ma YF, Jiang K. The role of ferroptosis in prostate cancer: a novel therapeutic strategy. Prostate Cancer P D 2023;26:25-29.
32. Koutcher J. Imaging Prostate Cancer (Pca) Phenotype and Evolution. Defense Technical Information Center 2015;U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012.
33. Yang CG, Ma XY, Wang ZH, Zeng X, Hu ZQ, Ye ZQ, et al. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation. Drug Des Dev Ther 2017;11:431-39.
34. Nick ALLWH. Growth Inhibition of Human Breast Cancer Cells with an Iron Chelator (Deferasirox) and Docetaxel, 2009: Cancer Research.
35. Ibrahim O, O'Sullivan J. Iron chelators in cancer therapy. Biometals 2020;33:201-15.
36. Tenuta A, Klotz L, Parker JL. Clinical trial risk in castration-resistant prostate cancer: immunotherapies show promise. Bju Int 2014;113:E82-E89.
37. Mannargudi MB, Deb S. Clinical pharmacology and clinical trials of ribonucleotide reductase inhibitors: is it a viable cancer therapy? J Cancer Res Clin 2017;143:1499-529.
38. (NCI) NCI. 3-AP in Treating Patients With Advanced Prostate Cancer, 2013.
39. Wang YF, Yu L, Ding J, Chen Y. Iron Metabolism in Cancer. International Journal of Molecular Sciences 2019;20.
40. Yin MM, Liu YP, Chen Y. Iron metabolism: an emerging therapeutic target underlying the anti-cancer effect of quercetin. Free Radical Res 2021;55:296-303.
41. Kovar J, Naumann PW, Stewart BC, Kemp JD. Differing sensitivity of non-hematopoietic human tumors to synergistic anti-transferrin receptor monoclonal antibodies and deferoxamine in vitro. Pathobiology 1995;63:65-70.
42. Dreicer R, Kemp JD, Stegink LD, Cardillo T, Davis CS, Forest PK, et al. A phase II trial of deferoxamine in patients with hormone-refractory metastatic prostate cancer. Cancer Invest 1997;15:311-17.
43. Carter A, Racey S, Veuger S. The Role of Iron in DNA and Genomic Instability in Cancer, a Target for Iron Chelators That Can Induce ROS. Appl Sci-Basel 2022;12.
44. Lui GYL, Kovacevic Z, Richardson V, Merlot AM, Kalinowski DS, Richardson DR. Targeting cancer by binding iron: Dissecting cellular signaling pathways. Oncotarget 2015;6:18748-79.
45. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer-the UK NCRN Pomi-T study. Prostate Cancer P D 2014;17:180-86.
46. Sanna V, Singh CK, Jashari R, Adhami VM, Chamcheu JC, Rady I, et al. Targeted nanoparticles encapsulating (-)-epigallocatechin-3-gallate for prostate cancer prevention and therapy. Sci Rep-Uk 2017;7.
47. Khan A, Singh P, Srivastava A. Iron: Key player in cancer and cell cycle? J Trace Elem Med Bio 2020;62.
48. Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and Cancer. Annual Review of Nutrition, Vol 38 2018;38:97-125.
49. Torti SV, Torti FM. Iron: The cancer connection. Mol Aspects Med 2020;75.
50. Morales M, Xue X. Targeting iron metabolism in cancer therapy. Theranostics 2021;11:8412-29.
51. Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Efficacy, Compliance and Toxicity Factors Are Affecting the Rate of Normalization of Body Iron Stores in Thalassemia Patients Using the Deferiprone and Deferoxamine Combination Therapy. Hemoglobin 2011;35:186-98.
52. Kontoghiorghe CN, Andreou N, Constantinou K, Kontoghiorghes GJ. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients. World J Methodol 2014;4:163-88.
53. Li PC, Zheng X, Shou KQ, Niu YH, Jian C, Zhao Y, et al. The iron chelator Dp44mT suppresses osteosarcoma's proliferation, invasion and migration: in vitro and in vivo. Am J Transl Res 2016;8:5370-85.
54. Yallapu MM, Khan S, Maher DM, Ebeling MC, Sundram V, Chauhan N, et al. Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer. Biomaterials 2014;35:8635-48.
55. Yan JK, Wang YZ, Zhang XF, Liu SD, Tian C, Wang HW. Targeted nanomedicine for prostate cancer therapy: docetaxel and curcumin co-encapsulated lipid-polymer hybrid nanoparticles for the enhanced anti-tumor activity and. Drug Deliv 2016;23:1757-62.
56. Han CL, Deng YX, Xu WC, Liu Z, Wang T, Wang SG, et al. The Roles of Tumor-Associated Macrophages in Prostate Cancer. J Oncol 2022;2022.
57. Leftin A, Ben-Chetrit N, Joyce JA, Koutcher JA. Imaging endogenous macrophage iron deposits reveals a metabolic biomarker of polarized tumor macrophage infiltration and response to CSF1R breast cancer immunotherapy. Sci Rep-Uk 2019;9.
58. Raymonvil AD. Serum iron concentration and prostate cancer in the United States., in College of Health Sciences2017, Walden University.
59. Merlot AM, Kalinowski DS, Kovacevic Z, Jansson PJ, Sahni S, Huang MLH, et al. Exploiting Cancer Metal Metabolism using Anti-Cancer Metal-Binding Agents. Current Medicinal Chemistry 2019;26:302-22.
60. Cao PHA, Dominic A, Lujan FE, Senthilkumar S, Bhattacharya PK, Frigo DE, et al. Unlocking ferroptosis in prostate cancer - the road to novel therapies and imaging markers. Nat Rev Urol 2024;21:615-37.
61. Bedford MR, Ford SJ, Horniblow RD, Iqbal TH, Tselepis C. Iron Chelation in the Treatment of Cancer: A New Role for Deferasirox? J Clin Pharmacol 2013;53:885-91.
62. Johnson IRD, Parkinson-Lawrence EJ, Shandala T, Weigert R, Butler LM, Brooks DA. Altered Endosome Biogenesis in Prostate Cancer Has Biomarker Potential. Mol Cancer Res 2014;12:1851-62.
63. Xiang DB, Zhou LL, Yang R, Yuan F, Xu YL, Yang Y, et al. Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy. Int J Nanomed 2024;19:2091-112.
64. Lin ZP, Ratner ES, Whicker ME, Lee Y, Sartorelli AC. Triapine Disrupts CtIP-Mediated Homologous Recombination Repair and Sensitizes Ovarian Cancer Cells to PARP and Topoisomerase Inhibitors. Mol Cancer Res 2014;12:381-93.

Details

Primary Language

English

Subjects

Biochemistry and Cell Biology (Other)

Journal Section

Systematic Reviews and Meta Analysis

Authors

Mesut Akyüz ^*
0000-0001-8161-2479
Türkiye

Elanur Aydın Karataş
0000-0001-8975-1932
Türkiye

Early Pub Date

December 11, 2025

Publication Date

December 13, 2025

Submission Date

August 25, 2025

Acceptance Date

October 11, 2025

Published in Issue

Year 2025 Volume: 4 Number: 2

DOI

https://doi.org/10.5281/zenodo.17786796

IZ

https://izlik.org/JA58GT52NB

APA

Akyüz, M., & Aydın Karataş, E. (2025). The Role of Iron Chelation Therapy in Prostate Cancer. Eurasian Journal of Molecular and Biochemical Sciences, 4(2), 116-132. https://doi.org/10.5281/zenodo.17786796

The Role of Iron Chelation Therapy in Prostate Cancer

Abstract

Keywords

References

Details

Primary Language

Subjects

Journal Section

Authors

Early Pub Date

Publication Date

Submission Date

Acceptance Date

Published in Issue

DOI

IZ

Cite