NF-kappa B kinetics predetermine TNF-alpha sensitivity of colorectal cancer cells

Background Tumour necrosis factor (TNF)-alpha has considerable anti-tumour activity and may have potential as a treatment for metastatic colorectal ca ncer. 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-kappa B is protective against TNF-alpha induced cell deat h, and this may explain tumour resistance. Methods In order to provide further understanding of determinants of TNF-al pha responses, we studied TNF-alpha induced NF-kappa B activation and varia ble tumour responses. We analysed the kinetics of TNF-alpha induced NF-kapp a B activation in colorectal cancer cells and determined whether it is poss ible to sensitize colorectal tumour cells to TNF-alpha by modulation of NF- kappa B signalling. Results We demonstrated that sustained NF-kappa B activation exceeding 16 h was observed in HRT18 and SW480 cells and was associated with TNF-alpha re sistance. In contrast, transient NF-kappa B activation in HCT116 cells was associated with sensitivity to cytotoxic TNF-alpha effects, suggesting that NF-kappa B kinetics may have utility as clinical marker of TNF-alpha tumou r resistance. Despite variable TNF-alpha responses and NF-kappa B kinetics, all three colorectal cancer cell lines were highly sensitive to treatment with the TNF-related apoptosis-inducing ligand (TRAIL) which induced only t ransient NF-kappa B activation. This further supports the notion of a pre-d etermined NF-kappa B response influencing receptor-mediated cell death. We also show that stable transfection and adenoviral-mediated expression of I kappa B(A32/36) can be used to confer TNF-alpha sensitivity to colorectal t umour cells previously resistant. Conclusions These findings indicate that a combined approach using gene the rapy and recombinant TNF-alpha merits further appraisal. Furthermore, the k inetics of the TNF-alpha response could be determined using a 'test-dose' t o indicate whether individual patients might benefit from this gene therapy approach. Copyright (C) 2000 John Wiley & Sons, Ltd.