title: Potential mechanisms of benzamide riboside mediated cell death.
abstract: Benzamide riboside (BR) after anabolism to an analogue of NAD, was shown to inhibit the activity of NAD-dependent enzymes such as inosine 5'-monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo guanylate biosynthesis, and malate dehydrogenase which is involved in the citric cycle and respiratory chain. BR exhibits strong anti-carcinogenic effects due to growth retardation and due to induction of apoptosis and necrosis. Apoptosis is ascribed to the inhibition of IMPDH because cell death can be blocked by restoring intracellular guanylate metabolism by the addition of guanosine. It is shown here, however, that also survival-relevant genes such as cdc25A, akt, bcl-2 and transferrin receptor become repressed by BR, whereas the expression level of the apoptosis enforcing gene c-myc persists. Even though BR-mediated growth retardation still allows BR to induce apoptosis, rapamycin-mediated cell cycle block and cell contact inhibition prevent cell death, it strongly suggests that BR induces a type of c-Myc-dependent apoptosis. At high concentrations BR induces DNA double strand breaks by yet to be determined mechanisms that occur hours before necrosis can be detected. This is accompanied by a dramatic decrease of intracellular ATP. The artificial restoration of ATP by addition of adenosine or sufficient provision of an energy source such as glucose prevents BR-promoted necrosis and favors apoptosis. This observation may be of clinical relevance.
authors.affiliation: Institute of Clinical Pathology, University of Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Polgar
authors.forename: Susanne
authors.initials: S
authors.lastname: Gfatter
authors.forename: Maria
authors.initials: M
authors.lastname: Uhl
authors.forename: Fekadu
authors.initials: F
authors.lastname: Kassie
authors.forename: Christina
authors.initials: C
authors.lastname: Leisser
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy*; D009705:Nucleosides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D009705:Nucleosides; C076145:3-(1-deoxyribofuranosyl)benzamide; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D005947:Glucose