Nuclear Factor-kB Tumor Expression Predicts Response and Survival in Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Irinotecan Therapy

Scartozzi, Mario; Bearzi, Italo; Pierantoni, Chiara; Mandolesi, Alessandra; Loupakis, Fotios; Zaniboni, Alberto; Catalano, Vincenzo; Quadri, Antonello; Zorzi, Fausto; Berardi, Rossana; Biscotti, Tommasina; Labianca, Roberto; Falcone, Alfredo; Cascinu, Stefano

doi:10.1200/jco.2007.11.5022

Cited by 116 publications

(69 citation statements)

References 21 publications

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“…4). Expression of this transcription factor, also activated by the EGFR downstream signaling pathway, has been associated with prognosis and resistance to antitumoral treatments in CRC and other solid tumors (46). These data stress as different responses to cetuximab are related to different sets of differentially expressed miRNAs and, accordingly, to different molecular signaling.…”

Section: Discussionmentioning

confidence: 87%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.

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Section: Discussionmentioning

confidence: 87%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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“…Constitutive NF-kB activation is found in most cancer cell lines and in numerous types of tumour tissues (Shishodia and Aggarwal 2004). Scartozzi et al (2007) reported that NF-kB nuclear expression predicts response and survival in irinotecan-refractory metastatic CRC treated with cetuximab -irinotecan therapy. These findings suggested that the tumour cell TLR4/MyD88 signalling pathway has a crucial role in CRC patient prognosis and that blocking this pathway could provide great benefits for patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

et al. 2010

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BACKGROUND: The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC). METHODS: The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed. RESULTS: Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P ¼ 0.0001, P ¼ 0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15 -4.07; P ¼ 0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31 -4.13; P ¼ 0.0038 and HR: 3.03; 95% CI: 1.67 -5.48; P ¼ 0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27 -3.99; P ¼ 0.0053 and HR: 2.97; 95% CI: 1.64 -5.38; P ¼ 0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99 -3.55; P ¼ 0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01 -3.67; P ¼ 0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17 -4.33; P ¼ 0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS. CONCLUSION: Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.

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“…The most likely reason that a combination of cytostatic and alpha lipoic acid exerts an inhibitory effect on the NF-κB levels would be strong antioxidant properties of the alpha lipoic acid, which thereby reduce the inducible effect. But the fact that the ALA applied solely and thus was not being able to completely suppress the synthesis and the activation of the NF-κB, acknowledges that cancer cells produce a constitutive NF-κB not only in response to the epigenetic factors (oxidative stress), but most likely as a mode for their survival (25,26,27). This is why it is inexplicable that the combined use of lipoic acid and 5-FU has resulted in increased effect of the cytostatic applied.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive potential of alpha lipoic acid in the treatment of colon and cervix cancer cell lines

Damnjanović¹,

Kocić²,

Najman³

et al. 2014

BLL

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Abstract:Objectives: The nuclear factor κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer. The aim of this study was to examine the infl uence of the alpha lipoic acid in the chemoprevention of colon and cervix carcinoma in vitro. Background: In recent years, special attention has been paid to the potential chemopreventive properties of antioxidants. There are no published data on the impact of alpha lipoc acid of chemoprevention of cervix and colon cancer. Methods: We examined the effect of alpha lipoic acid alone or in combination with cisplatin and 5-fl uorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. The measurement of the level of transcription factor NF-κB was also performed in the cells of both cell lines. Results: At least one of the mechanisms of the antiproliferative and/or cytotoxic effect of alpha lipoic acid on Caco-2 and HeLa cells at high concentrations, the transcription factor NF-κB, may be involved, as well as the products of transcription of genes that are under its control. Conclusion: The alpha lipoic acid has proven to be a promising candidate in the combat arena against cancer (Tab. 4, Ref. 31). Text in PDF www.elis.sk.

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Nuclear Factor-kB Tumor Expression Predicts Response and Survival in Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Irinotecan Therapy

Abstract: The difference in median TTP, overall survival, and response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab and irinotecan in advanced colorectal tumors.

Cited by 116 publications

References 21 publications

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

Chemopreventive potential of alpha lipoic acid in the treatment of colon and cervix cancer cell lines

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