Inhibition of doxorubicin-induced apoptosis in vivo by 2-deoxy-D-glucose.
Previous studies have shown that DNA cleavage by mammalian topoisomerase II is ATP dependent and can be inhibited by metabolic inhibitors. Furthermore, it has been shown that metabolic inhibitors also have a cytoprotective effect in vitro against topoisomerase II-targeting antitumor drugs. However, the nature of the ATP-dependent process is not known. We have previously shown that doxorubicin induces apoptosis (programmed cell death) in the murine small intestine which can be inhibited by the protein synthesis inhibitor cycloheximide. In the present study, we have demonstrated that 2-deoxy-D-glucose reduces the incidence of doxorubicin-induced apoptosis in vivo if administered within 45 min of the doxorubicin. Maximum reduction was observed at 2 h after treatment (approximately 66%); however, significant reduction was still observable at 9 h after treatment (approximately 33%). Significant positive correlation was observed between protein synthesis inhibition and apoptosis inhibition. Other possible mechanisms of action of the inhibitor do not appear to be important in cytoprotection. The inhibitor did not reduce the uptake of doxorubicin into the intestinal epithelium; however, it caused a significant increase in retention of the drug. The kinetics of inhibition suggest that alteration of cell cycle kinetics, inhibition of formation of doxorubicin-topoisomerase II complex or induction of glucose-regulated proteins are not significant factors in cytoprotection. These studies indicate that at least in the mouse small intestinal epithelium, the ATP-dependent process in cell killing by doxorubicin may involve protein synthesis.
Thakkar
N S
NS
CRC Department of Epithelial Biology, Paterson Institute of Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom.
Potten
C S
CS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D004249:DNA Damage; D003847:Deoxyglucose / Q000494:pharmacology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009696:Nucleic Acids / Q000096:biosynthesis; D014176:Protein Biosynthesis
D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D009696:Nucleic Acids; C018551:glucose-regulated proteins; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D003847:Deoxyglucose