title: 8-Chloroadenosine 3',5'-monophosphate induces cell cycle arrest and apoptosis in multiple myeloma cells through multiple mechanisms.
abstract: The aim of this study was to investigate the molecular mechanism of 8-chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) in the inhibition of the growth and induction of apoptosis of multiple myeloma (MM) cells. Two MM-derived cell lines, RPMI-8226 and U266, were used. Cell viability, apoptosis induction and mitochondrial transmembrane potential were determined and the expression levels of cell cycle regulatory proteins (Cdk2, cyclin E, p27 and c-myc) and p38 mitogen-activated protein kinase (MAPK) protein were detected. Following treatment with 8-Cl-cAMP, the percentage of apoptotic cells increased in a concentration- and time-dependent manner and the mitochondrial transmembrane potential collapsed to reveal typical apoptotic features. Our data further demonstrated that 8-Cl-cAMP induced progressive phosphorylation of p38 MAPK and that the expression levels of p27 proteins in the MM cells were increased whereas those of c-myc were significantly decreased. Notably, the proapoptotic effect of 8-Cl-cAMP was largely prevented by a p38 MAPK inhibitor. Furthermore, knockdown of p27 was able to decrease the 8-Cl-cAMP-induced apoptosis in the MM cells. These results indicate that 8-Cl-cAMP induced p27-dependent cell cycle arrest and apoptosis in the MM cells, which demonstrates the potential of cAMP-modulating agents for use in the treatment of MM.
authors.affiliation: Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011,  P.R. China.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Cheng
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Yao
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Wang
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Zou