Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches

Cheng, Xiaofei; Zhao, Feng; Ke, Bingxin; Chen, Dong; Liu, Fanlong

doi:10.3390/cancers15215209

Cited by 9 publications

(5 citation statements)

References 135 publications

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“…The field of GI cancer immunotherapy is rapidly evolving, with continuous investigations focusing on deciphering the intricacies of drug resistance and devising innovative approaches to overcome this hurdle. [ 57 ] The future of this field holds promise, but also presents challenges that need to be addressed. One of the potential future directions in this field is the development of personalized immunotherapies.…”

Section: Future Perspectivesmentioning

confidence: 99%

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

Yao,

Li,

Duan

et al. 2024

Medicine

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Gastrointestinal (GI) cancers pose a significant challenge due to high prevalence and mortality. While advancements in detection and conventional treatments have been made, prognosis often remains poor, particularly for advanced-stage cancers. Immunotherapy has emerged as a transformative approach, leveraging the body immune system against cancer, including immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer. These modalities have shown promise, achieving sustained responses and improved survival in some patients. However, their efficacy in GI cancers is less pronounced, hindered by drug resistance mechanisms that are either intrinsic or acquired over time. This review examines the latest understanding of immunotherapy in GI cancers, focusing on ICIs, cancer vaccines, and adoptive cell transfer, along with their associated outcomes and limitations. It delves into the mechanisms behind drug resistance, including alterations in immune checkpoints, the immunosuppressive tumor microenvironment, and genetic/epigenetic changes. The role of the gut microbiome is also considered as an emerging factor in resistance. To combat drug resistance, strategies such as enhancing immune response, targeting the tumor microenvironment, and modulating resistance mechanisms are explored. The review underscores the potential of ferroptosis induction as a novel approach. Looking forward, it highlights the need for personalized immunotherapies, understanding the influence of the gut microbiome, and further exploration of ferroptosis in overcoming resistance. While challenges persist, the continuous evolution in GI cancer immunotherapy research promises innovative treatments that could significantly improve patient outcomes.

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Section: Future Perspectivesmentioning

confidence: 99%

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

Yao,

Li,

Duan

et al. 2024

Medicine

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“…Additionally, GPX4 prevents ferroptosis, making it a potential target for therapeutic interventions, including cancer treatment (Forcina and Dixon, 2019). Due to frequent m6A and m5c modification of GPX4 in CRC, it is highly overexpressed (Chen B. et al, 2023;, leading to anti-cancer immunity (Chen B. et al, 2023), radiation resistance (Zhang et al, 2023c), and chemoresistance (Wang L. et al, 2023). The increased presence of GPX4 is detected in CRC persister cells resulting from exposure to anti-colorectal cancer drugs like 5-FU and AZ628.…”

Section: System XC − and Gpx4 Inhibitorsmentioning

confidence: 99%

“…Many articles have highlighted the significance of targeting ferroptosis for the treatment of colorectal cancer ( Zhang et al, 2023a ; Liang H. et al, 2023 ; Cheng et al, 2023 ; Liu et al, 2024 ). Therefore, this review aims to present a comprehensive perspective on the impact of natural products on proteins and pathways associated with ferroptosis in CRC ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting ferroptosis regulators by natural products in colorectal cancer

Zhang,

Xie

2024

Front. Pharmacol.

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Colorectal cancer (CRC) poses a significant global health challenge, ranking as the third most diagnosed cancer and the second leading cause of cancer-related deaths. Despite advancements in treatment, challenges such as delayed diagnosis, multidrug resistance, and limited therapeutic effectiveness persist, emphasizing the need for innovative approaches. This review explores the potential of natural products, nutraceuticals, and phytochemicals for targeting ferroptosis-related regulators as a novel strategy in CRC. Ferroptosis, a form of regulated cell death characterized by iron-dependent lethal lipid peroxide accumulation, holds substantial importance in CRC progression and therapy resistance. Natural products, known for their diverse bioactive effects and favorable safety profiles, emerge as promising candidates to induce ferroptosis in CRC cells. Exploring amino acid, iron, lipid metabolism regulators, and oxidative stress regulators reveals promising avenues for inducing cell death in CRC. This comprehensive review provides insights into the multifaceted effects of natural products on proteins integral to ferroptosis regulation, including GPX4, SLC7A11, ACSL4, NCOA4, and HO-1. By elucidating the intricate mechanisms through which natural products modulate these proteins, this review lays the foundation for a promising therapeutic strategy in CRC.

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“…In particular, several studies have suggested that aspirin is involved in the modulation of ferroptosis in many diseases, including chronic kidney disease and cancer [183][184][185][186]. Most importantly, the modulation of ferroptosis by aspirin has been suggested as a mechanism for the treatment of different untreated cancers, anticancer drug resistance, and metastasis [187][188][189][190][191][192][193][194]. Similarly, iron and other transition metal complexes of aspirin and aspirin-based compounds have been suggested as new anticancer agents [195].…”

Section: Interactions Of Aspirin (Acetylsalicylic Acid) and Its Glucu...mentioning

confidence: 99%

“…A major unexplored area of great importance in pharmacology and medicine is the effects of aspirin and ACM, as well as their iron complexes, on ferroptosis, which is a recently identified type of programmed cell death based on iron-catalysed lipid peroxidation damage of cell membranes [179][180][181][182][183][184]. Ferroptosis has been identified in almost all diseases, including cancer and neurodegeneration [179][180][181][182][183][184][185][186][187][188][189][190]. Several preliminary investigations have already implicated aspirin in the process of ferroptosis via different mechanisms [192][193][194].…”

Section: Future Studies and Limitations On The Role Of Aspirin In Iro...mentioning

confidence: 99%

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

Kontoghiorghes

2024

IJMS

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Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75–100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.

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Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches

Cited by 9 publications

References 135 publications

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

Targeting ferroptosis regulators by natural products in colorectal cancer

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

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