Modulation of radiation-induced apoptosis by thiolamines.
Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8.3 hybridoma after a 60-min (LD50 = 4.5 mM) or during a 20-h (LD50 = 0.15 mM) exposure. In contrast, a 20-h exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50% apoptosis within 20 h. Apoptosis was not induced by either a 60-min or 20-h exposure to 10 mM of the thiazolidine prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4 mM for 15 min) or cysteine (10 mM for 60 min) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 h) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 min beginning 60 min after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 h beginning 60 min after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.
Warters
R L
RL
Department of Radiation Oncology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
Roberts
J C
JC
Wilmore
B H
BH
Kelley
L L
LL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D003543:Cysteamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology*; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D006825:Hybridomas; D008624:Mercaptoethylamines / Q000494:pharmacology*; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D008624:Mercaptoethylamines; D011355:Prodrugs; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D003543:Cysteamine; D003545:Cysteine