β-adrenoceptor blockers protect against staurosporine-induced apoptosis in SH-SY5Y neuroblastoma cells

• Published in: European journal of pharmacology 2008-07, Vol.589 (1-3), p.14-21
• Main Authors: Mikami, Maya, Goubaeva, Farida, Song, Joseph H., Lee, H.T., Yang, Jay
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Apoptosis; Apoptosis - drug effects; Atenolol - pharmacology; Biological and medical sciences; Caspase; Caspase 3 - metabolism; Caspase 9 - metabolism; Caspase Inhibitors; Cell Line, Tumor; Cysteine Proteinase Inhibitors - pharmacology; Cytochromes c - metabolism; Cytoprotection; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; Humans; In Situ Nick-End Labeling; Medical sciences; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Neuroblastoma - enzymology; Neuroblastoma - pathology; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerases - metabolism; Propanolamines - pharmacology; Propranolol - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase Inhibitors - pharmacology; Staurosporine - pharmacology; Staurosporine, SH-SY5Y; Time Factors; β-adrenoceptor blocker
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.04.045

The β-adrenoceptor blockers exhibit a well-characterized anti-apoptotic property in the heart and kidney while less is known about the effect of this class of drugs on neuronal apoptosis. We studied the effects of three β-adrenoceptor blockers propranolol (1-(isoproplyamino)-3-(naphthalene-1-yloxy)propan-2-ol), atenolol (2-[4-[2-hydroxy-3-(1-methylethylamino)propoxyl]phenyl]ehanamide), and ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), against staurosporine-induced apoptosis in SH-SY5Y human neuroblastoma cells. Staurosporine increased caspase 3-like activity, DNA fragmentation, PARP cleavage, and the number of TUNEL positive cells consistent with the induction of apoptosis. Propranolol and ICI 118551, but not atenolol, demonstrated a concentration-dependent inhibition of caspase 3-like activity. Propranolol and ICI 118551 directly inhibited the enzymatic activity of recombinant caspase 9 while atenolol did not; however, none of the β-adrenoceptor blockers that were examined directly blocked caspases 2 or 3 activity. In isolated mitochondria, propranolol and ICI 118551 inhibited staurosporine-induced cytochrome c release while atenolol did not. We conclude that propranolol and ICI 118551 protect SH-SY5Y cells against staurosporine-induced apoptosis through a dual action on the mitochondria and on caspase 9 in a cell type and an apoptotic paradigm where the conventional inhibitors of mitochondrial permeability transition such as cyclosporin A and bongkrekic acid demonstrate no protection.