8-Chloro-cAMP induces apoptotic cell death in a human mammary carcinoma cell (MCF-7) line.
8-Cl-cAMP and 8-NH2-cAMP induced MCF-7 cell death. The type(s) of cell death were studied in more detail and compared with the cell death type (apoptosis) induced by okadaic acid, an inhibitor of serine/threonine phosphatases. By morphological criteria dying cells showed loss of cell-cell interactions and microvilli, condensation of nuclear chromatin and segregation of cytoplasmic organelles. By in situ nick end-labelling, using digoxigenin-conjugated dUTP as probe, a large fraction of 8-Cl-cAMP, 8-NH2-cAMP and 8-Cl-adenosine-exposed cells stained positively in the advanced stages of death. In the early phase of chromatin condensation the cells stained negatively. Specific (internucleosomal) DNA fragmentation was not observed. The MCF-7 cell death induced by 8-Cl-cAMP and 8-NH2-cAMP was not mediated by activation of the cAMP kinase since more stable cAMP analogues (8-CPT-cAMP and N6-benzoyl-cAMP) or forskolin failed to induce death. Furthermore, 8-Cl-cAMP action was counteracted by adenosine deaminase and 3-isobutyl-1-methylxanthine, and mimicked by 8-Cl-adenosine, a major metabolite of 8-Cl-cAMP. It is concluded that 8-Cl- and 8-NH2-cAMP can induce morphological and biochemical effects resembling apoptotic cell death in MCF-7 cells through their conversion into potent cytotoxic metabolite(s).
Bøe
R
R
Department of Anatomy and Cell Biology, University of Bergen, Norway.
Gjertsen
B T
BT
Døskeland
S O
SO
Vintermyr
O K
OK
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology*; D000243:Adenosine Deaminase / Q000494:pharmacology; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000473:pathology*; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004249:DNA Damage; D004988:Ethers, Cyclic / Q000494:pharmacology; D005260:Female; D006801:Humans; D008387:Marine Toxins; D008871:Microvilli / Q000187:drug effects; D008969:Molecular Sequence Data; D009336:Necrosis; D019319:Okadaic Acid; D015388:Organelles / Q000187:drug effects / Q000648:ultrastructure; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors
D002843:Chromatin; D004988:Ethers, Cyclic; D008387:Marine Toxins; D010080:Oxazoles; D005576:Colforsin; D019319:Okadaic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate; C050086:N(6)-benzoyl-cyclic AMP; C026661:8-aminoadenosine 3',5'-monophosphate; C059041:calyculin A; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D000243:Adenosine Deaminase; D015056:1-Methyl-3-isobutylxanthine