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Site‐selective cyclic AMP analogs provide a new approach in the control of cancer cell growth
Author(s) -
Katsaros Dionyssios,
Tortora Giampaolo,
Tagliaferri Pierosandro,
Clair Timothy,
Ally Shamsia,
Neckers Leonard,
Robins Roland K.,
Cho-Chung Yoon Sang
Publication year - 1987
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(87)80517-3
Subject(s) - adenosine , growth inhibition , cell growth , binding site , chemistry , stereochemistry , cancer cell , metabolite , active site , cell culture , biochemistry , biology , enzyme , cancer , genetics
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, N 6 ‐benzyl and N 6 ‐phenyl‐8‐ p ‐chlorophenylthio‐cAMP. The combination of a C‐8 with an N 6 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 R II cAMP receptor protein and a decrease of p21 ras protein. Since the adenosine counterpart of the 8‐chloro analog produced G 1 synchronization without affecting the R II 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.