beta-Adrenoceptor blockers protect against staurosporine-induced apoptosis in SH-SY5Y neuroblastoma cells.
The beta-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 beta-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 beta-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.
Department of Anesthesiology, Columbia University P & S, New York, NY 10032, USA.
Maya
M
Mikami
Farida
F
Goubaeva
Joseph H
JH
Song
H T
HT
Lee
Jay
J
Yang
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001262:Atenolol / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology*; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011412:Propanolamines; D047428:Protein Kinase Inhibitors; C026777:ICI 118551; D001262:Atenolol; D045304:Cytochromes c; D011433:Propranolol; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D019311:Staurosporine