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 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.
Lagadec
P
P
INSERM U526, Nice F-06000, France. lagadec@unice.fr
Griessinger
E
E
Nawrot
M P
MP
Fenouille
N
N
Colosetti
P
P
Imbert
V
V
Mari
M
M
Hofman
P
P
Czerucka
D
D
Rousseau
D
D
Berard
E
E
Dreano
M
M
Peyron
J F
JF
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C519899:AS602868; D000970:Antineoplastic Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D051550:I-kappa B Kinase; D002166:Camptothecin