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

British Journal of Cancer
Patricia LagadecJ F Peyron

Abstract

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 demon...Continue Reading

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Citations

Jun 25, 2010·Nutrition and Cancer·Jens E SlagsvoldSvanhild A Schønberg
Mar 17, 2017·International Journal of Molecular Sciences·Lovro ŽibernaSeyed Mohammad Nabavi
Sep 17, 2010·Cancer Chemotherapy and Pharmacology·Lars Petter JordheimCharles Dumontet
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Mar 20, 2018·Translational Research : the Journal of Laboratory and Clinical Medicine·Meera PatelJoanne Edwards

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Methods Mentioned

BETA
sumoylation
xenografts
ELISA
electrophoresis
xenograft
PMA

Software Mentioned

CompuSyn

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Apoptosis

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