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

NF-kappaB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kappaB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kappaB...

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Bibliographic Details
Published in:British journal of cancer 2008-01, Vol.98 (2), p.335
Main Authors: Lagadec, P, Griessinger, E, Nawrot, M P, Fenouille, N, Colosetti, P, Imbert, V, Mari, M, Hofman, P, Czerucka, D, Rousseau, D, Berard, E, Dreano, M, Peyron, J F
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Apoptosis - drug effects
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Cell Survival - drug effects
Colonic Neoplasms - drug therapy
Dose-Response Relationship, Drug
Drug Delivery Systems
Drug Synergism
Female
HT29 Cells
Humans
I-kappa B Kinase - antagonists & inhibitors
Irinotecan
Mice
Mice, Nude
NF-kappa B - antagonists & inhibitors
Protein Kinase Inhibitors - administration & dosage
Pyrimidines - administration & dosage
Topoisomerase I Inhibitors
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:NF-kappaB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kappaB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kappaB activation. In human colon cancer cells, inhibition of NF-kappaB using 10 microM 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-kappaB 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(-1) AS602868 associated with 30 mg kg(-1) 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-kappaB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFalpha 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.
ISSN:0007-0920