Inhibition of Colon Carcinogenesis by 2-Methoxy-5-Amino-N-Hydroxybenzamide, a Novel Derivative of Mesalamine

Stolfi, Carmine; Sarra, Massimiliano; Caruso, Roberta; Fantini, Massimo; Fina, Daniele; Pellegrini, Roberto; Palmieri, Giampiero; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.1053/j.gastro.2009.08.062

Cited by 16 publications

(31 citation statements)

References 32 publications

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“…The CAC model was induced as described previously (16,17) using azoxymethane (AOM; Sigma-Aldrich) and dextran sulfate sodium (DSS; Affymetrix). Male C57BL/6 mice (6-8 weeks) were randomly divided into 4 groups: control, embelin alone (embelin), CAC challenge (AOM/ DSS), and CAC challenge and embelin treatment (AOM/ DSSþembelin).…”

Section: Induction Of Colitis-associated Colon Cancermentioning

confidence: 99%

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

Dai

Jiao

Teng

et al. 2014

Molecular Cancer Therapeutics

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The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6-induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity. Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1b, IL-17a, and IL-23a expression as well as the number of CD4 þ T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC. Mol Cancer Ther; 13(5); 1206-16. Ó2014 AACR.

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Section: Induction Of Colitis-associated Colon Cancermentioning

confidence: 99%

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

Dai

Jiao

Teng

et al. 2014

Molecular Cancer Therapeutics

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“…Effect of 2-14 and TRAIL on the in vivo growth of CT26-derived tumors CT26-derived grafts were generated in BALB/c mice as described (25). After 2 weeks, mice with similar tumor volume, determined by caliper measurements, were divided into 4 groups of 8 mice each.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

“…Mice were sacrificed at day 28. Tumors were excised, photographed, their volume calculated as previously described (25), and used for immunofluorescence and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Studies were approved by the Local Ethics Committee.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

“…However, the antineoplastic effects of mesalamine are seen only with doses that are not always reached in the gut following oral administration of the drug (23,24). Therefore, we developed several derivatives of mesalamine and selected 2-14 as it was the more potent inhibitor of colon cancer cell growth (25). Because our previous study showed that treatment of colon cancer cell lines with 2-14 triggers endoplasmic reticulum stress (25), a phenomenon that has been involved in the regulation of the expression of various components of the TRAIL-driven apoptotic pathway (26,27), we hypothesized that 2-14 could restore the sensitivity of colon cancer cells to TRAIL.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we developed several derivatives of mesalamine and selected 2-14 as it was the more potent inhibitor of colon cancer cell growth (25). Because our previous study showed that treatment of colon cancer cell lines with 2-14 triggers endoplasmic reticulum stress (25), a phenomenon that has been involved in the regulation of the expression of various components of the TRAIL-driven apoptotic pathway (26,27), we hypothesized that 2-14 could restore the sensitivity of colon cancer cells to TRAIL. In this study, we assessed the in vitro and in vivo effect of 2-14 on TRAIL-induced colon cancer cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer Cells to TRAIL-Induced Apoptosis by Regulating Death Receptor 5 and Survivin Expression

Stolfi

Caruso

Franzè

et al. 2011

Molecular Cancer Therapeutics

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TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2-14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway-associated proteins and extracellular signal-regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL-mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro-and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2-14 to mice upregulated DR5 and downregulated survivin in a model of colitis-associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer. Mol Cancer Ther; 10(10); 1969-81. Ó2011 AACR.

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Colorectal Cancers

Parsyan

Robichaud

Meterissian

2014

Translation and Its Regulation in Cancer Biology and Medicine

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Colorectal cancers (CRCs) are malignancies with high incidence and mortality. Due to the introduction of screening programs leading to early diagnosis and treatment, a decrease in mortality from these cancers is being observed. However, therapeutic options for CRC, especially in advanced disease, are limited and require improvements. Development of targeted therapies based on the understanding of molecular alterations is a promising strategy. Our knowledge of the molecular environment that contributes to CRC is expanding. As research has progressed, we have come to realize that the protein biosynthesis pathway and its translational apparatus contribute significantly to cancer development and progression in Contents

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Inhibition of Colon Carcinogenesis by 2-Methoxy-5-Amino-N-Hydroxybenzamide, a Novel Derivative of Mesalamine

Cited by 16 publications

References 32 publications

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer Cells to TRAIL-Induced Apoptosis by Regulating Death Receptor 5 and Survivin Expression

Colorectal Cancers

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