The Role of Iron Chelation Therapy in Colorectal Cancer: A Systematic Review on Its Mechanisms and Therapeutic Potential

Abstract

Background: Despite significant therapeutic advancements in recent decades, colorectal cancer (CRC) continues to exhibit high rates of mortality and morbidity. Chemoresistance and cancer recurrence remain substantial challenges, underscoring the need for novel treatment approaches. Iron chelation therapy has gained profound interest over the years as a potential cancer treatment, leveraging the increased iron demand by tumors. This review evaluates the effects of iron chelation therapy on CRC progression and the underlying mechanisms.

Method: A comprehensive review of in vivo and in vitro studies was conducted to assess the effectiveness of iron chelation therapy in CRC. The literature search covered PubMed, Scopus, Medline (via Web of Science), and EMBASE between January 1995 and March 2024.

Results: Several in vitro and in vivo studies have investigated the impact of iron chelators, such as deferoxamine, deferasirox, thiosemicarbazone-based chelators, quilamine-based chelators, and other novel compounds on CRC. Natural plant extracts with iron-chelating properties have also been explored as potential treatments. Most studies indicate that iron chelation can inhibit the proliferation of colon cancer cells, though some studies suggest cancer-promoting effects. Mechanistically, iron chelation affects several hallmarks of CRC by modulating histone methylation, upregulating NDRG1, and influencing the Wnt/β-catenin and p53 signaling pathways. However, certain iron chelators may inhibit TRAIL-mediated apoptosis and activate the hypoxia-inducible factor (HIF), potentially accelerating CRC progression.

Conclusion: Future exploration of iron chelation therapy in CRC should focus on extensive in vitro, in vivo, and clinical studies to elucidate the precise mechanisms involved. A deeper understanding of the genetic and cellular alterations induced by iron chelation will enhance the development of effective therapeutic strategies for CRC.

Keywords: Colorectal cancer; anticancer effects; iron chelation; systematic review.

FIGURE 1

PRISMA flow diagram for study selection process: A total of 430 records were identified across four databases (Embase, PubMed, Scopus, and MEDLINE). After removing 142 duplicates, 288 records were screened, and 188 were excluded. Full texts of 100 studies were assessed for eligibility, with 53 further excluded due to being reviews, lacking full text, or having the wrong study design. Ultimately, 47 studies were included in the review.

FIGURE 2

Iron metabolism in CRC pathogenesis and progression. (a) Iron‐mediated CRC progression. High intracellular iron levels in the tumor cells lead to increased reactive oxygen species (ROS) synthesis, oncogene activation, pro‐inflammatory mediators, and dysbiosis. Reproduced via Biorender from Ref [36] with permission under a Creative Commons Attribution Licence (CC‐BY). (b) Iron metabolism in CRC. Transferrin receptors (TfR), labile iron pool (LIP), iron‐regulatory proteins (IRP), iron‐response elements (IRE), non‐transferrin‐bound iron (NTBI). (1) Transferrin‐bound iron binds to the plasma membrane's transferrin receptors (TfR). (2) Iron metabolism is controlled by iron‐regulatory proteins (IRP) at the cellular level. (3) Hepcidin is the main iron regulatory hormone that maintains systemic iron homeostasis. (4) High systemic iron levels can lead to Tf saturation. Hence, non‐transferrin‐bound iron (NTBI) formation follows. The uptake of NTBI can lead to the formation of reactive oxygen species (ROS), resulting in oxidative stress and cell damage. (5) In cancer cells, genes encoding proteins that increase intracellular iron (TfR, DMT1, hepcidin) are generally upregulated, whilst those decreasing iron levels (ferroportin) are downregulated. Reproduced via Biorender from Ref [46] with permission from Elsevier copyright [2014].

FIGURE 3

Schematic representations of the effects of iron chelation on CRC pathogenesis and progression. (a) Modulations in the Wnt/β‐catenin signaling pathway. Reproduced via Biorender from Ref. [100] with permission under a Creative Commons Attribution Licence (CC‐BY) copyright the authors[2020] (b) Upregulation of the p53 signaling pathway. Reproduced via Biorender from Ref [101] with permission under a Creative Commons Attribution Licence (CC‐BY) copyright the authors [2021]. (c) Alterations in autophagy (d) Upregulation of NDRG1. Reproduced via Biorender from Ref. [102] with permission copyright the authors [2013].

FIGURE 4

TRAIL‐mediated apoptosis pathway. Adapted from Ref. [131] with permission under a Creative Commons Attribution Licence (CC‐BY) copyright the authors [2023].