Targeting copper metabolism to defeat KRAS-driven colorectal cancer

Aubert, Laura; Nandagopal, Neethi; Roux, Philippe P.

doi:10.1080/23723556.2020.1822123

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…Recently, it was demonstrated that metabolic adaptions play an important role in highly resistant colorectal cancers with KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) mutation [ 115 ]. Strikingly, these profound metabolic dependencies were also linked to the addiction of KRAS-mutated cancer to Cu metabolism [ 116 , 117 ]. Profiling of KRAS-expressing intestinal epithelioid cells IEC-6 with the combination of state-of-the-art cell surface proteomics and CRISPR/Cas-9 screens identified ATP7A as a lethal synthetic partner in KRAS-mutant colorectal cancers [ 116 ].…”

Section: Tumor Modulation With Inorganic Cu Saltsmentioning

confidence: 99%

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

2021

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Copper (Cu) is a vital element required for cellular growth and development; however, even slight changes in its homeostasis might lead to severe toxicity and deleterious medical conditions. Cancer patients are typically associated with higher Cu content in serum and tumor tissues, indicating increased demand of cancer cells for this micronutrient. Cu is known to readily cycle between the +1 and +2 oxidation state in biological systems. The mechanism of action of Cu complexes is typically based on their redox activity and induction of reactive oxygen species (ROS), leading to deadly oxidative stress. However, there are a number of other biomolecular mechanisms beyond ROS generation that contribute to the activity of anticancer Cu drug candidates. In this review, we discuss how interfering with intracellular Cu balance via either diet modification or addition of inorganic Cu supplements or Cu-modulating compounds affects tumor development, progression, and sensitivity to treatment modalities. We aim to provide the rationale for the use of Cu-depleting and Cu-overloading conditions to generate the best possible patient outcome with minimal toxicity. We also discuss the advantages of the use of pre-formed Cu complexes, such as Cu-(bis)thiosemicarbazones or Cu-N-heterocyclic thiosemicarbazones, in comparison with the in situ formed Cu complexes with metal-binding ligands. In this review, we summarize available clinical and mechanistic data on clinically relevant anticancer drug candidates, including Cu supplements, Cu chelators, Cu ionophores, and Cu complexes.

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Section: Tumor Modulation With Inorganic Cu Saltsmentioning

confidence: 99%

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

2021

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“…Accumulated copper ions play a crucial role in CRC progression (Aubert, Nandagopal, Roux, 2020; Aubert, Nandagopal, Steinhart, Lavoie, et al, 2020; Feng et al, 2009; Ishida et al, 2013; Liao et al, 2020; Sen et al, 2001; Shanbhag et al, 2021). To remove intracellular copper ions, copper chelators, such as TM and trientine, have been used to demonstrate the efficacy of this “starvation strategy” (Alvarez et al, 2010; Baldari et al, 2019; Brem et al, 2005; Brewer, 2014; Hyvönen et al, 2016; Jain et al, 2013; Zhang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that the inflammatory response induces copper uptake through an IL‐17‐STEAP4‐XIAP axis, which promotes tumorigenesis of colorectal cancer (CRC) (Liao et al, 2020). Kirsten rat sarcoma viral oncogene (KRAS) mutated CRC cells acquire copper via a noncanonical mechanism involving macropinocytosis to support their growth, revealing copper metabolism to be a promising therapeutic target for the suppression of KRAS‐driven colorectal cancer (Aubert, Nandagopal, Roux, 2020; Aubert, Nandagopal, Steinhart, Lavoie, et al, 2020). Elevated copper levels were also found to regulate the expression of vascular endothelial growth factor (VEGF) and hypoxia‐inducible factor‐1 (HIF‐1), thus stimulating tumor angiogenesis (Feng et al, 2009; Sen et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A novel copper chelator for the suppression of colorectal cancer

Shi

Liu

Jia

et al. 2023

Drug Development Research

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Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called "JYFY-001" that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRCtransplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice.Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.

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“…In ovarian cancer and non-small cell lung cancer, the activity and expression of copper-associated transporters are involved in the formation of tumor resistance to cisplatin and other platinum compounds ( 14 ). In COAD, the formation of KRAS-induced tumor and the generation of drug resistance are related to copper metabolism, and the use of copper chelating agent can inhibit the growth of tumor cells ( 17 ). In addition, copper-associated metabolic proteins can enhance the sensitivity of COAD cell lines to oxaliplatin ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Copper metabolism patterns and tumor microenvironment characterization in colon adenocarcinoma

Lin

Luo

et al. 2022

Front. Oncol.

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Copper participates in biological processes such as oxygen metabolism and iron uptake, and is a key factor in immune regulation. Based on the transcription data, mutation data and clinical data of colon adenocarcinoma (COAD) patients from The Cancer Genome Atlas (TCGA) database and Gene Expression Profiling Interactive Analysis (GEPIA2) database, the expression and mutation of copper metabolization-related genes in COAD patients and their correlation with tumor immune microenvironment were analyzed. Copper metabolization-related genes (CMRGs) were used to construct COAD subtypes and prognostic risk models for COAD patients. Furthermore, Kaplan-Meier (K-M) curve and receiver operating characteristic (ROC) curve were used to analyze the clinical value of COAD subtypes and genotyping models in distinguishing clinical characteristics of patients, and the immune infiltration of patients with different genotypes was analyzed. Finally, the clinical tissue samples from COAD patients were used to analyze the mRNA expression of genes in risk model between tumor and normal tissues by the method of Polymerase Chain Reaction (PCR). Of the 479 CMRGs, 68 genes were differentially expressed in normal and tumor tissues of COAD patients in TCGA and GEPIA2. Two subtypes with different clinical and immunological characteristics were identified by using 482 genes related to copper metabolism. Finally, a prognostic risk model consisting of five CMRGs was constructed, which could not only predict the prognosis of patients, but also correlated with COAD subtypes. In addition, some genes (glutathione S-transferase mu 1, cyclin D1and cytochrome P450 family 2 subfamily S member 1) in risk model was show significant difference between normal and tumor tissues. The COAD subtypes identified by CMRGs can help clinically distinguish patients with different prognosis and tumor progression, and the risk score can assist in clinical evaluation of patient prognosis, serving as a valuable biomarker for COAD immunotherapy.

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Targeting copper metabolism to defeat KRAS-driven colorectal cancer

Cited by 5 publications

References 10 publications

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

A novel copper chelator for the suppression of colorectal cancer

Copper metabolism patterns and tumor microenvironment characterization in colon adenocarcinoma

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