Inhibition of doxorubicin-induced apoptosis in vivo by 2-deoxy-D-glucose.
AffiliationCRC Department of Epithelial Biology, Paterson Institute of Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom.
MetadataShow full item record
AbstractPrevious 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.
CitationInhibition of doxorubicin-induced apoptosis in vivo by 2-deoxy-D-glucose. 1993, 53 (9):2057-60 Cancer Res.
- Abrogation of adriamycin toxicity in vivo by cycloheximide.
- Authors: Thakkar NS, Potten CS
- Issue date: 1992 Apr 15
- Apoptosis induced by anthracycline antibiotics in P388 parent and multidrug-resistant cells.
- Authors: Ling YH, Priebe W, Perez-Soler R
- Issue date: 1993 Apr 15
- Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection.
- Authors: Demidenko ZN, Vivo C, Halicka HD, Li CJ, Bhalla K, Broude EV, Blagosklonny MV
- Issue date: 2006 Sep
- Topoisomerase inhibitor camptothecin sensitizes mouse hepatocytes in vitro and in vivo to TNF-mediated apoptosis.
- Authors: Hentze H, Latta M, Künstle G, Dhakshinamoorthy S, Ng PY, Porter AG, Wendel A
- Issue date: 2004 May
- Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation.
- Authors: Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS
- Issue date: 2003 Jun 6