Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappa B activation

Limited studies have indicated that some chemotherapy agents activate the t ranscription factor nuclear factor-kappa B (NF-kappa B), and that this lead s to suppression of the apoptotic potential of the chemotherapy, In contras t, it was reported recently that stable inhibition of NF-kappa B in four di fferent cancer cell lines did not lead to augmentation of the chemotherapy- induced apoptosis. In this study, we have focused on colorectal cancer, whi ch is known to be highly resistant to genotoxic chemotherapy and gamma irra diation. We show that the topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperi dino)-1-piperidino]carbon (CPT-11) activates NF-kappa B in most colorectal cancer cell lines. We then examine a therapeutic strategy that uses adenovi rus-mediated transfer of the super-repressor I kappa B alpha to inhibit NF- kappa B activation as an adjuvant approach to promote chemosensitivity in c olorectal tumor cells to treatment with CPT-II, These data demonstrate that the protection from apoptosis induced in response to CPT-11 treatment is e ffectively inhibited by the transient inhibition of NF-kappa B 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 i nduction of apoptosis, These findings indicate that the activation of NF-ka ppa B by chemotherapy is an important underlying mechanism of inducible che moresistance.