The transcription factor NF-kB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that di er in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 mM) and doxorubicin (0.3 mM): Highly sensitive BxPC-3 and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kB activity in all cell lines, whereas basal NF-kB binding was nearly undetectable in BxPc-3 and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkBa super-repressor, strongly enhanced the apoptotic e ects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kB activity rather than the transient induction of NF-kB by some anti-cancer drugs. Blockade of basal NF-kB activity by well established drugs e ciently reduces chemoresistance of pancreatic cancer cells and o ers the potential for improved therapeutic strategies. Oncogene (2001) 20, 859 ± 868.
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