Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species

Fatfat, Maamoun; Merhi, Raghida Abou; Rahal, Omar Nasser; Stoyanovsky, Detcho A.; Zaki, Angela M.; Haidar, Hazar; Kagan, Valerian E.; Gali‐Muhtasib, Hala; Machaca, Khaled

doi:10.1186/1471-2407-14-527

Cited by 88 publications

(68 citation statements)

References 38 publications

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“…7). TPEN, a known cytotoxic compound (38)(39)(40), was used as a positive control and showed toxicity at concentrations of Ͼ3.75 M, in agreement with previous findings (38,39). Most cyclic peptomers were not cytotoxic to HeLa cells, except for EpD-4=N, which showed toxicity at concentrations of Ͼ102 M. In addition, EpD-1N-treated cells displayed low absorbance in the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay at all concentrations, for reasons that are unclear but may reflect the compound's physical properties under these conditions.…”

Section: Development and Use Of An Nf-b-gfp Stable Cell Line For Idenmentioning

confidence: 99%

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

Lam

Schwochert

Lao

et al. 2017

Antimicrob Agents Chemother

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Antibiotic-resistant bacteria are an emerging threat to global public health. New classes of antibiotics and tools for antimicrobial discovery are urgently needed. Type III secretion systems (T3SS), which are required by dozens of Gramnegative bacteria for virulence but largely absent from nonpathogenic bacteria, are promising virulence blocker targets. The ability of mammalian cells to recognize the presence of a functional T3SS and trigger NF-B activation provides a rapid and sensitive method for identifying chemical inhibitors of T3SS activity. In this study, we generated a HEK293 stable cell line expressing green fluorescent protein (GFP) driven by a promoter containing NF-B enhancer elements to serve as a readout of T3SS function. We identified a family of synthetic cyclic peptide-peptoid hybrid molecules (peptomers) that exhibited dose-dependent inhibition of T3SS effector secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa without affecting bacterial growth or motility. Among these inhibitors, EpD-3=N, EpD-1,2N, EpD-1,3=N, EpD-1,2,3=N, and EpD-1,2,4=N exhibited strong inhibitory effects on translocation of the Yersinia YopM effector protein into mammalian cells (Ͼ40% translocation inhibition at 7.5 M) and showed no toxicity to mammalian cells at 240 M. In addition, EpD-3=N and EpD-1,2,4=N reduced the rounding of HeLa cells caused by the activity of Yersinia effector proteins that target the actin cytoskeleton. In summary, we have discovered a family of novel cyclic peptomers that inhibit the injectisome T3SS but not the flagellar T3SS.

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Section: Development and Use Of An Nf-b-gfp Stable Cell Line For Idenmentioning

confidence: 99%

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

Lam

Schwochert

Lao

et al. 2017

Antimicrob Agents Chemother

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“…3C), which acts to saturate TPEN and inhibit its effects. Having shown previously that saturation with copper sulfate did not block cellular toxicity at high TPEN concentrations, 18 we investigated whether increasing the concentration of TPEN to 15 mM in the presence of 5 mM copper sulfate would still cause DNA damage. We found that, at such high concentrations of TPEN, DNA damage was not reversed and the activation levels of p-Chk1, p-ATM and g-H2AX were high despite the presence of copper sulfate (Fig.…”

Section: Dna Damage By Tpen Is Dependent On Redox Cycling Of Coppermentioning

confidence: 99%

“…18 Therefore, we aimed to determine whether DNA damage induced by TPEN is dependent on the redox cycling of copper. To this end we assessed DNA damage in TPEN treated HCT116 cells under 2 different conditions: first by treating cells with copper sulfate which saturates TPEN with exogenous copper thus preventing its binding to intracellular copper, and second by depleting intracellular copper using the copper specific chelator Neo.…”

Section: Dna Damage By Tpen Is Dependent On Redox Cycling Of Coppermentioning

confidence: 99%

“…13 If the damage is excessive or DNA repair is ineffective, then activation of cell death is the normal physiological response. 12 Although TPEN has been found to inhibit proliferation and induce apoptosis in many cell systems including lymphocytes, 14 epithelial cells, 15 hepatocytes, 16 breast cancer, 17 HT-29 colorectal cancer, 18,19 splenocytes, ovarian cancer, prostate cancer, 20 and pancreatic cancer, 21 its DNA damage potential and mechanisms remain unclear. We have previously shown that the generation of ROS and the redox cycling of copper following TPEN treatment result in targeted cell death of HCT116 human colon cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that the generation of ROS and the redox cycling of copper following TPEN treatment result in targeted cell death of HCT116 human colon cancer cells. 18 Here we investigated for the first time the effect of TPEN on DNA damage and the signaling molecules involved in the cellular response to damage. We found that TPEN induces DNA damage and activates ATM/ATR signaling, which is critically dependent on increased intracellular ROS production.…”

Section: Introductionmentioning

confidence: 99%

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Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Rahal

Fatfat

Hankache

et al. 2016

Cancer Biology & Therapy

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Recently, we showed that the metal chelator TPEN targets colon cancer cells through redox cycling of copper. Here, we studied the DNA damage potential of TPEN and deciphered the role of Chk1, ATM and DNA-PK in TPEN-induced toxicity in 3 human colon cancer cell lines, HCT116, SW480 and HT29. We also investigated the role of reactive oxygen species (ROS) in TPEN-induced DNA damage. TPEN reduced cell viability in a dose-and time-dependent manner. Cytotoxicity was associated with significant DNA damage and higher expression of g-H2AX protein and activation of ATM/ATR signaling pathway. Cell death by TPEN was dependent on ROS generation as evidenced by the reversal of cell viability, and DNA damage and the abrogation of g-H2AX levels in the presence of antioxidants. Treatment with antioxidants, however, failed to reverse cytotoxicity at high TPEN concentrations (10mM). TPEN-induced cell death was also dependent on the redox cycling of copper since the copper chelator neocuproine inhibited DNA damage and reduced pChk1, g-H2AX, and ATM protein expression. Cell death by low TPEN concentrations, involved ATM/ATR signaling in all 3 cell lines, since pre-incubation with specific inhibitors of ATM and DNA-PK led to the recovery of cells from TPEN-induced DNA damage. In addition, siRNA silencing of Chk1, DNA-PK and ATM abrogated the expression of g-H2AX and reversed cell death, suggesting that Chk1 and DNA-PK mediate TPEN-induced cytotoxicity in colon cancer cells. This study shows for the first time the involvement of Chk1, DNA-PK and ATM in TPEN-induced DNA damage and confirms our previous findings that ROS generation and the redox cycling of copper in response to TPEN are the main mechanisms by which this compound induces cell death in human colon cancer cells. Inhibition of ATM or DNA-PK did not reverse cytotoxicity at high TPEN concentrations that cause excessive levels of ROS and irreversible cellular damage.Abbreviations: ROS, reactive oxygen species; XIAP, X-linked inhibitor of apoptosis; DNA-PK, DNA-dependent protein kinase; ATM, ataxia telangiectasia mutated; ATR, serine/threonine protein kinase ataxia telangiectasia; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DCFH, 2 0 ,7 0 -Dichlorofluorescin diacetate; NAC, N-acetyL-cysteine; CAT, catalase; DSB, double strand break; SSB, single strand break; Neo, neocuproine; PI, propidium iodide; DDR, DNA damage response

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Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

Wang,

Pei,

Yang

et al. 2024

Clinical & Translational Med

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Copper, a trace element and vital cofactor, plays a crucial role in the maintenance of biological functions. Recent evidence has established significant correlations between copper levels, cancer development and metastasis. The strong redox‐active properties of copper offer both benefits and disadvantages to cancer cells. The intestinal tract, which is primarily responsible for copper uptake and regulation, may suffer from an imbalance in copper homeostasis. Colorectal cancer (CRC) is the most prevalent primary cancer of the intestinal tract and is an aggressive malignant disease with limited therapeutic options. Current research is primarily focused on the relationship between copper and CRC. Innovative concepts, such as cuproplasia and cuproptosis, are being explored to understand copper‐related cellular proliferation and death. Cuproplasia is the regulation of cell proliferation that is mediated by both enzymatic and nonenzymatic copper‐modulated activities. Whereas, cuproptosis refers to cell death induced by excess copper via promoting the abnormal oligomerisation of lipoylated proteins within the tricarboxylic acid cycle, as well as by diminishing the levels of iron‐sulphur cluster proteins. A comprehensive understanding of copper‐related cellular proliferation and death mechanisms offers new avenues for CRC treatment. In this review, we summarise the evolving molecular mechanisms, ranging from abnormal intracellular copper concentrations to the copper‐related proteins that are being discovered, and discuss the role of copper in the pathogenesis, progression and potential therapies for CRC. Understanding the relationship between copper and CRC will help provide a comprehensive theoretical foundation for innovative treatment strategies in CRC management.

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Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species

Cited by 88 publications

References 38 publications

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

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