Growth inhibitory effects of ATP and its derivatives on human fibroblasts immortalized with 60Co-gamma rays.
In our previous study (Katayama B et al, Int J Mol Med 2: 603-606, 1998), cell growth inhibition caused by ATP added to cultures was found to be greater in immortalized human fibroblasts than in the normal human fibroblasts. Since it has been reported that ATP affects cells via P2-purinergic receptors, growth inhibitory effects of ATP and its derivatives on immortalized human fibroblasts were investigated in the present study in order to learn what type of receptors are involved in ATP cytotoxicity. The ATP derivatives used in this study were: ATP, ADP, beta, gamma-methyleneadenosine 5'-triphosphate (MeATP), 2' & 3'-o-(4-benzoylbenzoyl) adenosine, triethylammonium salt (BzATP), adenosine 5'-o-(3-thiotriphosphate) (ATPgammaS), 2-methylthioadenosine 5'-triphosphate (2-MeSATP) and UTP. The extent of cytotoxicity induced by these drugs was found to be in the order of: ATP=ADP>ATPgammaS>MeATP=BzATP. On the other hand, neither 2-MeSATP nor UTP showed any cytotoxicity. These findings indicate that ATP may exert the cell growth inhibition by certain kinds of signal transduction via P2x or P2y purinergic receptors which affect intrinsic channels/pores of cell membrane and/or G protein activation. As a result, intracellular elevation in the concentrations of ions such as calcium and potassium, membrane depolarization, loss of endogenous ions/metabolites, and activation of inositol phospholipid-specific phospholipase C may occur. Actually, a dihydropyridine calcium channel blocker, nifedipine, and an ATP-sensitive K+-channel blocker, glybenclamide, reduced the growth inhibitory effects of ATP on the cells to some extent. The growth inhibition caused by ATP was not due to apoptosis or induction of a cyclin/CDK kinase inhibitor, P21.
Li
J W
JW
Department of Cell Biology, Institute of Cellular and Molecular Biology, Okayama University Medical School, Okayama 700-8558, Japan.
Inoue
Y
Y
Miyazaki
M
M
Pu
H
H
Kondo
A
A
Namba
M
M
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000528:radiation effects; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D005720:Gamma Rays; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism
D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D009543:Nifedipine; D005905:Glyburide