Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets

Wang, Yunhan; Zhang, Zongying; Sun, Wenping; Zhang, Jie; Xu, Qiuyun; Zhou, Xiaorong; Mao, Liming

doi:10.1016/j.biopha.2022.113524

Cited by 49 publications

(28 citation statements)

References 217 publications

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“…Ferroptosis is a programmed cell death caused by the accumulation of lethal lipid peroxides. − GSH is the main antioxidant in cells and the preferred GPX4 substrate. Therefore, the insufficient supply of GSH directly affects GPX4 function, resulting in ferroptosis. , Regarding biochemical characteristics, ferroptosis is characterized by GSH depletion, GXP4 inactivation, and lipid peroxide accumulation.…”

Section: Resultsmentioning

confidence: 99%

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis

Ding,

Sun,

et al. 2023

ACS Omega

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A series of novel canthin-6-one (CO) derivatives (8a–l) were designed and synthesized by introducing different amide side chains at the C-2 position, and their water solubility, antiproliferative activity, and preliminary mechanism were investigated. Most compounds displayed high cytotoxicity exhibiting low-micromolar IC50 values against four human cancer cell lines, especially HT29 cells. Meanwhile, the water solubility of active CO derivatives was significantly improved. Among these compounds, compound 8h with the N-methyl piperazine group exhibiting the highest antiproliferative capability with an IC50 value of 1.0 μM against HT29 cells, which was 8.6-fold lower than that of CO. Furthermore, 8h could upregulate the levels of reactive oxygen species, leading to mitochondrial damage. In addition, 8h could promote cell apoptosis and DNA damage by regulating the expression of apoptosis-associated proteins (Bcl-2 and cleaved-caspase 3) and the DNA damage-associated protein (H2AX). Most importantly, 8h also exerted ferroptosis by reducing the GSH level and GPX4 expression as well as increasing the lipid peroxidation level. Thus, the novel CO derivative 8h with N-methylpiperazine represents a promising anticancer candidate and warrants a more intensive study.

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Section: Resultsmentioning

confidence: 99%

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis

Ding,

Sun,

et al. 2023

ACS Omega

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“…Several naturally occurring compounds have been considered important to assess these unmet needs in metastatic CRC treatment because of their multi-targeted efficacy and time-tested safety compared to conventional drugs [ 5 , 7 , 8 ]. Ferroptosis is a unique type of programmed cell death depending on the intracellular accumulation of iron, followed by enhanced production of reactive oxygen species (ROS) and lipid peroxides [ 5 , 18 , 19 ]. Recently, ferroptosis has been considered an endogenous anticancer mechanism and is actively being studied to develop novel therapeutic targets in cancer [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Ferroptosis is a unique type of programmed cell death process that depends on the intracellular accumulation of iron, followed by enhanced production of reactive oxygen species (ROS) and lipid peroxides, eventually promoting iron-dependent cell death in cancer cells [ 5 , 18 , 19 ]. Recently, ferroptosis has been considered an endogenous anticancer mechanism and is actively being studied to develop novel therapeutic targets in cancer [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1

Miyazaki

Shimada

et al. 2023

Pharmaceuticals

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Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.

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“…Elevated iron concentration makes cells more sensitive to ferroptosis. About 60% of CRC patients are iron deficient, and those with iron deficiency have a poorer prognosis and are less responsive to treatment (Wang et al, 2022). Thus, appropriate iron supplementation is of great benefit to the Frontiers in Pharmacology frontiersin.org treatment and prognosis of CRC patients (Aksan et al, 2021).…”

Section: Ferroptosis and Colorectal Cancermentioning

confidence: 99%

Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

Zhang

Lv²,

Wang³

2023

Front. Pharmacol.

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Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxidation and resultant membrane damage. Recent research has elucidated the mechanism of ferroptosis and investigated the relationship between ferroptosis and various diseases, including degenerative diseases, cancer, and inflammation. Ferroptosis is associated with inflammation-related intestinal diseases such as colitis and colitis-associated cancer. New insights into the role of ferroptosis in the pathogenesis of inflammation-related gut diseases have suggested novel therapeutic targets. In this review, we summarize current information on the molecular mechanisms of ferroptosis and describe its emerging role and therapeutic potential in inflammation-related intestinal diseases.

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Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets

Cited by 49 publications

References 217 publications

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis

Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1

Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

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