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NF-kappaB kinetics predetermine TNF-alpha sensitivity of colorectal cancer cells.

Zwacka, RM and Stark, L and Dunlop, MG (2000) 'NF-kappaB kinetics predetermine TNF-alpha sensitivity of colorectal cancer cells.' J Gene Med, 2 (5). 334 - 343. ISSN 1099-498X

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BACKGROUND: Tumour necrosis factor (TNF)-alpha has considerable anti-tumour activity and may have potential as a treatment for metastatic colorectal cancer. However, TNF-alpha responses in patients and cell lines are variable and TNF-alpha treatment is associated with dose limiting clinical toxicity. Activation of NF-kappaB is protective against TNF-alpha induced cell death, and this may explain tumour resistance. METHODS: In order to provide further understanding of determinants of TNF-alpha responses, we studied TNF-alpha induced NF-kappaB activation and variable tumour responses. We analysed the kinetics of TNF-alpha induced NF-kappaB activation in colorectal cancer cells and determined whether it is possible to sensitize colorectal tumour cells to TNF-alpha by modulation of NF-kappaB signalling. RESULTS: We demonstrated that sustained NF-kappaB activation exceeding 16 h was observed in HRT18 and SW480 cells and was associated with TNF-alpha resistance. In contrast, transient NF-kappaB activation in HCT116 cells was associated with sensitivity to cytotoxic TNF-alpha effects, suggesting that NF-kappaB kinetics may have utility as clinical marker of TNF-alpha tumour resistance. Despite variable TNF-alpha responses and NF-kappaB kinetics, all three colorectal cancer cell lines were highly sensitive to treatment with the TNF-related apoptosis-inducing ligand (TRAIL) which induced only transient NF-kappaB activation. This further supports the notion of a pre-determined NF-kappaB response influencing receptor-mediated cell death. We also show that stable transfection and adenoviral-mediated expression of IkappaB(A32/36) can be used to confer TNF-alpha sensitivity to colorectal tumour cells previously resistant. CONCLUSIONS: These findings indicate that a combined approach using gene therapy and recombinant TNF-alpha merits further appraisal. Furthermore, the kinetics of the TNF-alpha response could be determined using a 'test-dose' to indicate whether individual patients might benefit from this gene therapy approach.

Item Type: Article
Uncontrolled Keywords: Adenoviridae, Apoptosis, Apoptosis Regulatory Proteins, Colorectal Neoplasms, DNA-Binding Proteins, Drug Resistance, Gene Expression, Genetic Therapy, Humans, I-kappa B Proteins, Kinetics, Membrane Glycoproteins, NF-KappaB Inhibitor alpha, NF-kappa B, TNF-Related Apoptosis-Inducing Ligand, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 29 Jun 2017 20:07
Last Modified: 02 Sep 2019 23:15

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