β2-adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction

Abstract

The stimulation of β2-adrenoceptor, which is a major mediator for chronic stress-induced cancers, has been implicated in the progression in the number of cancer cells, including pancreatic cancer, which remains one of the most aggressive and lethal diseases worldwide. Whether β-adrenoceptor antagonists potentiate gemcitabine, a standard first-line treatment for advanced pancreatic cancer that offers only modest benefit due to acquired chemoresistance, has not been elucidated. Thus, we studied the antiproliferative and apoptotic effects and the underlying mechanisms of gemcitabine combined with the β2-adrenoceptor blocker ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), in human pancreatic cancer BxPC-3 and MIA PaCa-2 cells. Results show that ICI 118551 significantly synergized the antiproliferative and pro-apoptotic effects induced by gemcitabine in both BxPC-3 and MIA PaCa-2 cells (P<0.05 combination vs. control or gemcitabine alone). When cells were treated with the combination of gemcitabine and ICI 118551, NF-κB activation was blocked; the expression of Bax protein was substantially increased; and Bcl-2 protein was downregulated. Taken together, the data suggest that ICI 118551 potentiates the antiproliferative effects of gemcitabine by inducing apoptosis in pancreatic cancer cells. Our study implies that this combination may be an effective therapeutic strategy for pancreatic cancer.