Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.
The transcription factor NF-kappaB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 microM) and doxorubicin (0.3 microM): Highly sensitive T3M4 [corrected] 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-kappaB activity in all cell lines, whereas basal NF-kappaB binding was nearly undetectable in T3M4 [corrected] 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-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkappaBalpha super-repressor, strongly enhanced the apoptotic effects 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-kappaB activity rather than the transient induction of NF-kappaB by some anti-cancer drugs. Blockade of basal NF-kappaB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.
Arlt
A
A
Laboratory of Molecular Gastroenterology, 1st Department of Medicine, University of Kiel, Germany.
Vorndamm
J
J
Breitenbroich
M
M
Fölsch
U R
UR
Kalthoff
H
H
Schmidt
W E
WE
Schäfer
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D005912:Gliotoxin / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D007976:Leupeptins / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012460:Sulfasalazine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D012460:Sulfasalazine; D005912:Gliotoxin; D005047:Etoposide; D004317:Doxorubicin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde