Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation.
Limited studies have indicated that some chemotherapy agents activate the transcription factor nuclear factor-kappaB (NF-kappaB), and that this leads to suppression of the apoptotic potential of the chemotherapy. In contrast, it was reported recently that stable inhibition of NF-kappaB in four different cancer cell lines did not lead to augmentation of the chemotherapy-induced apoptosis. In this study, we have focused on colorectal cancer, which is known to be highly resistant to genotoxic chemotherapy and gamma irradiation. We show that the topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) activates NF-kappaB in most colorectal cancer cell lines. We then examine a therapeutic strategy that uses adenovirus-mediated transfer of the super-repressor IkappaBalpha to inhibit NF-kappaB activation as an adjuvant approach to promote chemosensitivity in colorectal tumor cells to treatment with CPT-11. These data demonstrate that the protection from apoptosis induced in response to CPT-11 treatment is effectively inhibited by the transient inhibition of NF-kappaB in a variety of human colon cancer cell lines and in a tumor xenograft model, resulting in a significantly enhanced tumoricidal response to CPT-11 via increased induction of apoptosis. These findings indicate that the activation of NF-kappaB by chemotherapy is an important underlying mechanism of inducible chemoresistance.
Cusack
J C
JC
Department of Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7210, USA.
Liu
R
R
Baldwin
A S
AS
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D000077146:Irinotecan; D002166:Camptothecin