Cytotoxic Effect of Cholesterol Metabolites on Human Colonic Tumor (Caco-2) and Non-Tumor (CCD-18Co) Cells and Their Potential Implication in Colorectal Carcinogenesis

Unabsorbed cholesterol, along with that of bile secretions and flaked colon cells, can be metabolized by colonic microbiota. The generated metabolites have been proposed as promoters of colorectal cancer (CRC). In this study, the cytotoxicity (MTT assay) of the main commercially available cholesterol-derived metabolites (coprostanol, cholestanol, coprostanone, and cholestenone) on human colon cancer (Caco-2) and non-tumor (CCD-18Co) cells was evaluated at different physiologically relevant concentrations (9.4–300 µM) and incubation times (24–72 h). In general, the metabolites that most reduced cell viability were coprostanone (54–85% in Caco-2 and 20–81% in CCD- 18Co) and cholestenone (17–91% in Caco-2 and 14–81% in CCD-18Co). These two metabolites are the most hydrophobic, thus reflecting a possible relationship between hydrophobicity and cytotoxicity. Moreover, cholestenone (IC50 at 72 h: 5 ± 1 µg/mL) should be considered cytotoxic on CCD- 18Co cells (non-tumor cells) since it shows an IC50 close to the one considered toxic (<4 µg/mL). Furthermore, CCD-18Co cells are more vulnerable to the cytotoxic effect of cholesterol metabolites. Possible compensatory responses, attenuating the reduction in cell viability caused by cholesterol metabolites, were observed, however these reactions could favor inflammation, resistance to apoptosis, and cellular proliferation, likely contributing to the development of CRC. In conclusion, cholesterol metabolites, mainly the most hydrophobic, could act as promoters of CRC through their cytotoxic activity.

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MicroRNA-511 Inhibits Cellular Proliferation and Invasion in Colorectal Cancer by Directly Targeting Hepatoma-Derived Growth Factor

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504018x15154094331876 ◽

2018 ◽

Vol 26 (9) ◽

pp. 1355-1363 ◽

Cited By ~ 4

Author(s):

Saifei He ◽

Guangdong Wang ◽

Jing Ni ◽

Juhua Zhuang ◽

Suiliang Zhuang ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Cell Lines ◽

Cellular Proliferation ◽

Human Colon ◽

Colorectal Carcinogenesis ◽

Normal Human ◽

Direct Target ◽

Tumor Types ◽

Proliferation And Invasion

Dysregulated microRNA (miRNA) expression is involved in the occurrence and development of colorectal cancer (CRC) through the regulation of various important physiological events. Hence, miRNAs may be used as effective targets for CRC treatment; however, this hypothesis warrants further investigation. miRNA-511 (miR-511) plays vital roles in the progression of different tumor types. However, the expression, exact role, and the mechanisms underlying the regulation of colorectal carcinogenesis and progression by miR-511 remain poorly understood. This study presents that miR-511 expression was decreased in CRC tissues and cell lines compared with that in adjacent nonneoplastic tissues and normal human colon epithelium cell lines, respectively. The enforced expression of miR-511 in CRC cells significantly reduced cell proliferation and invasion. Hepatoma-derived growth factor (HDGF) was mechanically validated as a direct target of miR-511 in CRC. Furthermore, miR-511 was negatively associated with HDGF in CRC tissues. The restored HDGF expression can abrogate the tumor-suppressive roles of miR-511 in CRC cells. More importantly, miR-511 overexpression suppressed the PI3K/AKT signaling pathway in CRC. These results suggest that miR-511 can potentially serve as a therapeutic target for the therapy of patients with CRC.

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RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer

Cancers ◽

10.3390/cancers13133192 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3192

Author(s):

Antoine Gleizes ◽

Mouna Triki ◽

Sandrine Bonnet ◽

Naomi Baccari ◽

Gabriel Jimenez-Dominguez ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Differentiation ◽

Paneth Cell ◽

Wnt Signaling Pathway ◽

Cell Lineage ◽

Human Colon ◽

Luciferase Reporter ◽

Loss Of Function ◽

Sox9 Expression ◽

Human Colon Cancer

RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.

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Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells

BMC Cancer ◽

10.1186/s12885-021-08188-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Helena de Castro e Gloria ◽

Laura Jesuíno Nogueira ◽

Patrícia Bencke Grudzinski ◽

Paola Victória da Costa Ghignatti ◽

Temenouga Nikolova Guecheva ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Mismatch Repair ◽

Cell Cycle Progression ◽

Combined Therapy ◽

Combined Treatment ◽

Human Colon ◽

Human Colon Cancer

Abstract Background The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. Methods Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. Results Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. Conclusion Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

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Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice

International Journal of Oncology ◽

10.3892/ijo_00000007 ◽

1992 ◽

Cited By ~ 5

Author(s):

Irit Gil-Ad

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cell Lines ◽

Human Colon ◽

Colon Cancer Cell ◽

Human Colon Cancer Cell ◽

Human Colon Cancer ◽

Colon Cancer Cell Lines ◽

Anti Cancer ◽

Cancer Activity

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PEGylated Active Carbon Nanoparticles with Improved Dispersivity in Water and Potential Application in Lymphatic Targeted Therapy of Colorectal Cancer

Journal of Nano Research ◽

10.4028/www.scientific.net/jnanor.66.85 ◽

2021 ◽

Vol 66 ◽

pp. 85-102

Author(s):

Wen Kai Liu ◽

Yuan Qing Song ◽

Yan Ma ◽

Xin Li ◽

Peng Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Active Carbon ◽

Potential Application ◽

Carbon Nanoparticles ◽

Drug Loading ◽

Human Colon ◽

Tumor Treatment ◽

Human Colon Cancer ◽

Pegylated Nanoparticles ◽

Improved Stability

A series of PEGylated active carbon nanoparticles were fabricated with improved dispersity in water and were explored for their ability for carrying drugs and potential application in lymphatic targeted tracing and chemotherapy of colorectal cancer. The active carbon nanoparticles were oxidized in a mild condition with 30% H2O2 solution and then mPEG-NH2 was grafted to the nanoparticles. Compared with the original carbon nanoparticles, the oxidized and PEGylated nanoparticles all present improved stability and initial solubility in water and the PEGylated nanoparticles perform best. Size of the nanoparticles was well controlled in a rational area which can fulfill the requirement for lymphatic targeting. The PEGylated nanoparticles have excellent drug loading properties and allow for sustained release under physiological conditions. The MTT results show the drug-loaded nanoparticles can effectively kill SW480 cells (Human Colon Cancer Cells). These characteristics make the PEGylated nanoparticles become a promising candidate for using as drug-loaded powder for both lymphatic targeted tracing and chemo-therapy without using suspending agent in tumor treatment.

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Evaluation of the Genotoxic and Oxidative Damage Potential of Silver Nanoparticles in Human NCM460 and HCT116 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21051618 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1618 ◽

Cited By ~ 6

Author(s):

Mingxi Jia ◽

Wenjing Zhang ◽

Taojin He ◽

Meng Shu ◽

Jing Deng ◽

...

Keyword(s):

Oxidative Damage ◽

Food Packaging ◽

Antibacterial Properties ◽

Human Colon ◽

Ag Nps ◽

Damage Potential ◽

Human Colon Cancer ◽

Colon Cells ◽

Antibacterial Textiles ◽

The Many

Nano Ag has excellent antibacterial properties and is widely used in various antibacterial materials, such as antibacterial medicine and medical devices, food packaging materials and antibacterial textiles. Despite the many benefits of nano-Ag, more and more research indicates that it may have potential biotoxic effects. Studies have shown that people who ingest nanoparticles by mouth have the highest uptake in the intestinal tract, and that the colon area is the most vulnerable to damage and causes the disease. In this study, we examined the toxic effects of different concentrations of Ag-NPs on normal human colon cells (NCM460) and human colon cancer cells (HCT116). As the concentration of nanoparticles increased, the activity of the two colon cells decreased and intracellular reactive oxygen species (ROS) increased. RT-qPCR and Western-blot analyses showed that Ag NPs can promote the increase in P38 protein phosphorylation levels in two colon cells and promote the expression of P53 and Bax. The analysis also showed that Ag NPs can promote the down-regulation of Bcl-2, leading to an increased Bax/Bcl-2 ratio and activation of P21, further accelerating cell death. This study showed that a low concentration of nano Ag has no obvious toxic effect on colon cells, while nano Ag with concentrations higher than 15 μg/mL will cause oxidative damage to colon cells.

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Nei Endonuclease VIII-Like1 (NEIL1) Inhibits Apoptosis of Human Colorectal Cancer Cells

BioMed Research International ◽

10.1155/2020/5053975 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Wanjuan Xue ◽

Yongcheng Liu ◽

Ningning Xin ◽

Jiyu Miao ◽

Juan Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Human Colon ◽

Caspase 9 ◽

Human Colon Cancer ◽

Expression Levels ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

The study is aimed at investigating the role of Nei endonuclease VIII-like1 (NEIL1) in the pathogenesis of colorectal cancer (CRC). The human CRC (HCT116 and SW480) cells were subjected to the siRNA silencing and recombinant plasmid overexpression of NEIL1. Transfection of siNEIL1 significantly inhibited the cell growth. It also increased the Bax expression levels, while it decreased the Bcl-2 expression levels in human CRC cells, leading the Bax/Bcl-2 balance toward apoptosis. Moreover, the apoptosis was promoted through the caspase-9 signaling pathway. One the other hand, high expression of NEIL1 promoted the cell viability and reduced the apoptosis, inducing the balance of Bax/Bcl-2 in the human colon cancer cells to be antiapoptotic. In addition, the caspase-9 signaling pathway inhibited apoptosis, contrary to the results obtained by downregulating NEIL1 expression. Furthermore, NEIL1 was negatively regulated by miR-7-5p, indicating that miR-7-5p inhibited the NEIL1 expression after transcription. Overexpression of miR-7-5p reversed the effects of NEIL1 on these CRC cells. In conclusion, NEIL1 promotes the proliferation of CRC cells, which is regulated negatively by miR-7-5p. These findings suggest that NEIL1 is a potential therapeutic target for CRC.

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Colorectal Cancer Study with Nanostructured Sensors: Tumor Marker Screening of Patient Biopsies

Nanomaterials ◽

10.3390/nano10040606 ◽

2020 ◽

Vol 10 (4) ◽

pp. 606 ◽

Cited By ~ 1

Author(s):

Michele Astolfi ◽

Giorgio Rispoli ◽

Gabriele Anania ◽

Veronica Nevoso ◽

Elena Artioli ◽

...

Keyword(s):

Colorectal Cancer ◽

Principal Component ◽

Human Colon ◽

Diagnostic Methods ◽

Human Colon Cancer ◽

Discrimination Power ◽

Tissue Samples ◽

Chemoresistive Sensors ◽

One Year ◽

Nanostructured Sensors

Despite the great progress in screening techniques and medical treatments, colorectal cancer remains one of the most widespread cancers in both sexes, with a high death rate. In this work, the volatile compounds released from human colon cancer tissues were detected by a set of four different chemoresistive sensors, made with a nanostructured powder of metal-oxide materials, inserted into an innovative patented device. The sensor responses to the exhalation of a primary cancer sample and of a healthy sample (both of the same weight, collected during colorectal surgery from the intestine of the same patient) were statistically analyzed. The sensors gave reversible, reproducible, and fast responses for at least one year of continuous use, making them quite superior in respect to the existing diagnostic methods. Preliminary results obtained using principal component analysis of the sensor responses to samples removed from 13 patients indicate that the nanostructured sensors employed in this study were able to distinguish between healthy and tumor tissue samples with coherent responses (the discrimination power of the most sensitive sensor was about 17%), highlighting a strong potential for clinical practice.

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Animal models of gastrointestinal and liver diseases. New mouse models for studying dietary prevention of colorectal cancer

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00019.2014 ◽

2014 ◽

Vol 307 (3) ◽

pp. G249-G259 ◽

Cited By ~ 4

Author(s):

James C. Fleet

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Mouse Models ◽

Human Colon ◽

Low Grade ◽

Preclinical Models ◽

Dietary Interventions ◽

Single Model ◽

Human Colon Cancer ◽

Molecular Etiology

Colorectal cancer is a heterogeneous disease that is one of the major causes of cancer death in the U.S. There is evidence that lifestyle factors like diet can modulate the course of this disease. Demonstrating the benefit and mechanism of action of dietary interventions against colon cancer will require studies in preclinical models. Many mouse models have been developed to study colon cancer but no single model can reflect all types of colon cancer in terms of molecular etiology. In addition, many models develop only low-grade cancers and are confounded by development of the disease outside of the colon. This review will discuss how mice can be used to model human colon cancer and it will describe a variety of new mouse models that develop colon-restricted cancer as well as more advanced phenotypes for studies of late-state disease.

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