title: Novel growth inhibitory effect of 8-Cl-cAMP is dependent on serum factors that modulate protein kinase A expression but not the hydrolysis of 8-Cl-cAMP.
abstract: 8-Chloro-cyclic AMP (8-Cl-cAMP) exhibits growth inhibition in vitro and in vivo in a broad spectrum of cancer cell lines. We examined whether the hydrolyzed metabolite is involved in the effect of 8-Cl-cAMP. 8-Cl-cAMP (5 mu M, 3 days) exerted varying degrees (0-51%) of growth inhibition on the same cell line cultured in the medium containing different heat-inactivated serum. HPLC analysis neither detected 8-Cl-adenosine in the medium nor demonstrated any correlation between the decrease in 8-Cl-cAMP concentration in the medium and the degree of growth inhibition. The low K-m phosphodiesterase activity in the sera did not correlate with the varying degrees of growth inhibition. The cAMP-dependent protein kinase RI(alpha) subunit expression in the same cell line varied widely with the different serum supplements. 8-Cl-CAMP-, but not 8-Cl-adenosine-induced, growth inhibition correlated with the basal levels of RI(alpha) and specific downregulation of RI(alpha). 8-Cl-cAMP, but not 8-Cl-phenyl-thio-cAMP or N-6-benzyl-cAMP, inhibited cell growth in serum-free medium. These results show that 8-Cl-cAMP induces growth inhibition through down-regulation of protein kinase A type I in the absence of its hydrolysis.
authors.affiliation: NCI,CELLULAR BIOCHEM SECT,TUMOR IMMUNOL & BIOL LAB,BETHESDA,MD 20892. US FDA,CLIN PHARMACOL BRANCH,BETHESDA,MD 20892. TERUMO CO LTD,KANAGAWA,JAPAN. SMITH KLINE BEECHAM PHARMACEUT,WELWYN GARDEN CIT,HERTS,ENGLAND.
authors.forename: A
authors.initials: A
authors.lastname: Budillon
authors.forename: T
authors.initials: T
authors.lastname: Clair
authors.forename: N
authors.initials: N
authors.lastname: Hartman
authors.forename: J
authors.initials: J
authors.lastname: Strong
authors.forename: Y
authors.initials: Y
authors.lastname: Sobukawa
authors.forename: K
authors.initials: K
authors.lastname: Miki
authors.forename: A
authors.initials: A
authors.lastname: Worby
authors.forename: K
authors.initials: K
authors.lastname: Murray
authors.forename: Y
authors.initials: Y
authors.lastname: Chochung