Inhibition of NF-Kappa B augments sensitivity to 5-Fluorouracil/Folinic acid in colon cancer1

Voboril, R; Hochwald, Steven N.; Li, Jing; Brank, Adam; Weberová, Jana; Wessels, Frank J.; Moldawer, Lyle L.; Camp, E. Ramsay; MacKay, Sally L. D.

doi:10.1016/j.jss.2003.11.023

Cited by 56 publications

(35 citation statements)

References 29 publications

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“…Inhibition of NF-kB was also observed to reveal an apoptotic action of TNFa on HT-29 cells, whose intratumoural concentrations were increased upon CPT-11 treatment. Furthermore, in agreement with previous data (Wang et al, 2003;Voboril et al, 2004), inhibition of NF-kB also augmented sensitivity of HT-29 tumour cells to 5-FU, the most common antimetabolite used for the treatment of CRC and other types of solid tumours.…”

Section: Discussionsupporting

confidence: 92%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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NF-kB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kB activation. In human colon cancer cells, inhibition of NF-kB using 10 mM AS602868 induced a 30 -50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg À1 AS602868 associated with 30 mg kg À1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFa on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours.

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Section: Discussionsupporting

confidence: 92%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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“…Furthermore, it is activated by chemotherapy and it represents one of the most important mechanism of cell survival in response to chemotherapy resulting in resistance to treatment (Lind et al, 2001;Rakitinat et al, 2003;Sclabas et al, 2003;Guo et al, 2004;Voboril et al, 2004;Karin, 2006). In our study, activation of NF-kB was present in four cases.…”

Section: Discussionsupporting

confidence: 51%

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Cascinu

Berardi

Salvagni³

et al. 2007

Br J Cancer

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Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib þ FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate ¼ 34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.

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“…In fact, 5-FU was described to induce activation of NF-kB in two colon cancer cell lines and four out of five TS inhibitor-resistant colon cancer cell lines were found to overexpress NF-kB mRNA and protein levels . Moreover, Voboril et al (2004) recently demonstrated that the inhibition of NF-kB enhanced the cytotoxic effect of 5-FU also in colon cancer cells. The chemo-sensitizing effect of Src kinase inhibition might also be associated with other 5-FU-resistance-associated enzymes, such as thymidine phosphorylase or orotate phosphoribosyl transferase.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling

et al. 2008

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Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU þ Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU þ PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

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Inhibition of NF-Kappa B augments sensitivity to 5-Fluorouracil/Folinic acid in colon cancer1

Cited by 56 publications

References 29 publications

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling

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