1. ¹Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA
2. ²Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL, USA

Correspondence: Dr SM Sebti, Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. E-mail: sebti@moffitt.usf.edu

Received 20 March 2006; Revised 11 October 2006; Accepted 17 October 2006; Published online 29 January 2007.

Abstract

A chemical biology approach identifies a beta 2 adrenergic receptor (2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. 2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. 2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. 2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that 2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, 2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.