Inhibition of doxorubicin-induced cell death in vitro and in vivo by cycloheximide.
We studied the effects of the protein synthesis inhibitor, cycloheximide (CH), on cell killing by doxorubicin (DOX) in vitro and in vivo. At the concentration of CH used (1 microgram/ml) the cytotoxicity of DOX was reduced in cultured P388 leukemia cells. An analysis of the DNA histogram obtained by flow cytometry showed that DOX exerts its growth-inhibitory effect by blocking the cell cycle at the G2/M phase in P388 cells. Treatment with CH diminished this blocking effect. When CH was added to the growth medium before DOX exposure, no change in intracellular DOX accumulation was observed. Treatment with CH (15 mg/kg) significantly diminished the lethality of DOX (20 mg/kg) in mice and it also reduced the antitumor activity of mice with P388 leukemia. Thus, CH inhibited cell death induced by DOX in vitro and in vivo. These results suggest that CH has an antagonistic effect on the pharmacological actions of DOX in cells and mice. The cytoprotective effect of CH may be due to protein synthesis inhibition.
Furusawa
S
S
Department of Pharmacology and Toxicology, Tohoku College of Pharmacy, Sendai, Japan.
Nakano
S
S
Kosaka
K
K
Takayanagi
M
M
Takayanagi
Y
Y
Sasaki
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D007941:Leukemia P388 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009580:Nitroblue Tetrazolium; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D009580:Nitroblue Tetrazolium; D004317:Doxorubicin; D003513:Cycloheximide