Dual anticancer activity of 8-Cl-cAMP: inhibition of cell proliferation and induction of apoptotic cell death.
8-Cl-cAMP induces apoptotic cell death in human cancer cells. To look at this more closely, we examined the changes in the levels of Bcl-2 family proteins during 8-Cl-cAMP-induced apoptosis of SH-SY5Y human neuroblastoma cells. Following the treatment with 8-Cl-cAMP, Bcl-2 was transiently down-regulated and Bad was increased continuously up to day 5. In addition, overexpression of Bcl-2 efficiently blocked the 8-Cl-cAMP-induced apoptosis, suggesting Bcl-2 family proteins may be involved in the 8-Cl-cAMP-induced apoptosis. The contribution of the apoptotic cell death and the inhibition of cell proliferation in the 8-Cl-cAMP-induced growth inhibition was closely monitored in the Bcl-2-overexpressing cells. Though the apoptosis was reduced significantly, no significant difference was observed in the inhibition of cell proliferation up to day 2 of 8-Cl-cAMP treatment. These results suggest that 8-Cl-cAMP exerts anticancer activity by two distinct mechanisms, i.e. , through the inhibition of cell proliferation as well as the induction of apoptosis. Supporting this notion was the observations that (1) suppression of apoptosis by zVAD did not abrogate 8-Cl-cAMP-induced inhibition of cell proliferation, and (2) 8-Cl-cAMP did not show additive inhibition of cell proliferation in RIIbeta-overexpressing cells.
Kim
S N
SN
School of Biological Sciences, Seoul National University, Seoul, 151-742, Republic of Korea.
Kim
S G
SG
Park
J H
JH
Lee
M A
MA
Park
S D
SD
Cho-Chung
Y S
YS
Hong
S H
SH
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; C517837:PRKAR2B protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases