Inhibition of NF-kappa B sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

The transcription factor NF-kappaB has anti-apoptotic properties and may co nfer chemoresistance to cancer cells. Here, me describe human pancreatic ca rcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 muM) and doxorubicin (0.3 muM): Highly sensitive BxPC- 3 and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistan t to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kappaB activity in all cell lines, whereas basal NF-kappaB 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. Trea tment with various NF-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine ), or transfection with the I kappaB alpha super-repressor, strongly enhanc ed the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 81 8-4 cells. Our results indicate that under certain conditions the resistanc e of pancreatic carcinoma cells to chemotherapy is due to their constitutiv e NF-kappaB activity rather than the transient induction of NF-kappaB by so me anti-cancer drugs. Blockade of basal NF-kappaB activity by well establis hed drugs efficiently reduces chemoresistance of pancreatic cancer cells an d offers the potential for improved therapeutic strategies.