Purpose: Pancreatic cancer is characterized by an extremely poor prognosis due to the aggressive disease course and lack of effective therapeutic intervention. IkappaB kinase (IKK), a central kinase for nuclear factor-kappaB (NF-kappaB) activation, is often constitutively activated in pancreatic cancer cells, playing a crucial role in the malignant phenotype and resistance to anti-cancer agents. This study explored how specific inhibition of IKKbeta suppresses oncogenic proliferation of pancreatic cancer cells.
Experimental design: We employed two different approaches, RNA interference-mediated depletion of IKKbeta (IKKbetai) and use of a novel molecularly designed IKKbeta inhibitor IMD-0354 to investigate the effects on the in vitro and in vivo growth and apoptotic response of pancreatic cancer cells.
Results: IKKbetai and IMD-0354 efficiently suppressed constitutive NF-kappaB activity and the growth of pancreatic cancer cells in monolayer and soft agar. IMD-0354 induced Annexin V expression, a typical apoptotic cell response. Notably, daily administration of IMD-0354 significantly suppressed tumor growth in NOD/SCID/gamma c(null) (NOG) mice without any deleterious side effect.
Conclusions: These results identify IKKbeta as an attractive molecular target for pancreatic cancer therapy.