Site‐selective cyclic AMP analogs provide a new approach in the control of cancer cell growth

Abstract

Site-selective cyclic AMP analogs bind to site 1 or site 2 of the known cAMP-binding sites depending on the position of substituents on the purine ring, either at C-2 and C-8 (site 1) or at C-6 (site 2). The growth inhibitory effect of such site-selective cAMP analogs used in this investigation with 15 human cancer cell lines surpassed that of analogs previously tested. The most potent analogs were 8-chloro, N6-benzyl and N6-phenyl-8-p-chlorophenylthio-cAMP. The combination of a C-8 with an N6 analog had synergistic effects. The 24 site-selective analogs tested produced growth inhibition ranging from 30 to 80% at micromolar concentrations with no sign of toxic effects. Growth inhibition was not due to a block in a specific phase of the cell cycle but paralleled a change in cell morphology, an increase of the RII cAMP receptor protein and a decrease of p21 ras protein. Since the adenosine counterpart of the 8-chloro analog produced G1 synchronization without affecting the RII and p21 ras protein levels, it is unlikely that an adenosine metabolite is involved in the analog effect. Site-selective cAMP analogs thus provide a new biological tool for control of cancer growth.

Dual Anticancer Activity of 8-Cl-cAMP: Inhibition of Cell Proliferation and Induction of Apoptotic Cell Death

“…Suppression of type I PKA using antisense oligonucleotide against RI␣ mRNA successfully induced growth inhibition of cancer cells in vitro and in vivo (3,4). A group of site-selective cAMP analogues inhibited cell growth in a variety of cancer cells and induced differentiation in leukemic cells (5,6). In addition, introduction of RII␤ subunit of PKA, which resulted in the increase of type II PKA and the downregulation of type I PKA, suppressed growth and transformed phenotype of transformed or cancer cells (7)(8)(9).…”

A novel cell-based assay for the evaluation of anti-ras compounds

“…Differential expression of type I and type II protein kinase isoenzymes has been shown to affect cell growth and differentiation (Gharret et al, 1976;Russell, 1978;ChoChung, 1980) and certain analogues of c-AMP including 8-bromo cAMP have been shown to modulate this differential expression in a spectrum of cancer cell lines (Katsaros et al, 1987;Ally et al, 1989). The latter authors also showed that treatment with the compound decreased both N-ras and c-myc mRNA levels in lung tumours.…”

Interactions of the Protein Kinase A Signaling Pathway: Implications for the Treatment of Endocrine and Other Tumors

“…Ally, S.; Tortora, G.; Clair, T.; Grieco, D.; Merlo, G.; Katsaros, D.;Ogreid, D.;Doskeland, S.O. ;Jahnsen, T. & Cho-Chung, Y.S.…”

“…However, their mechanisms of action were debated. Questions asked were: 1) does 8-CL-ADO have inhibitory effects on cell growth in human thyroid, HeLa and other tumor cell types; 2) does 8-Cl-ADO act on adenosine receptors to stimulate adenyl cyclase and PKA activity; 3) are the inhibitory effects of 8-Cl-cAMP due to its by-product 8-Cl-ADO; and 4) does 8-Cl-ADO exert its inhibitory effects by changing the RI to RII subunit ratio as has been suggested for 8-Cl-cAMP (Katsaros et al, 1987;Robinson-White et al, 2008). In [ 3 H] thymidine uptake and Cell Titer 96 AQ (MST) cell proliferation assays using human thyroid tumor cells (WRO), HeLa cells and other cancer cell types (colon carcinoma/ARO and melanoma/ NPA) both 8-CL-cAMP and 8-Cl-ADO inhibit cell growth and proliferation (IC 50 values ranged from 0.5 M to 1.7 M for 8-CL-ADO and 0.55 M to 4.4 M with 8-Cl cAMP, depending on the cell type).…”

“…PKA activity is stimulated by cAMP and its cAMP analogues. One such analogue, the 8-Cl-derivative of cAMP (8-Cl-CAMP), the most potent of the cAMP analogues initially tested (Katsaros et al, 1987), and its dephosphorylated metabolite, 8-Cl-ADO are known inhibitors of cancer cell proliferation. However, their mechanisms of action were debated.…”