Maintenance of ATP favours apoptosis over necrosis triggered by benzamide riboside.
A new synthetic drug, benzamide riboside (BR) exhibited strong oncolytic activity against leukemic cells in the 5-10 microM range. Higher BR-concentrations (20 microM) predominantly induced necrosis which correlated with DNA strand breaks and subsequent depletion of ATP- and dATP levels. Replenishment of the ATP pool by addition of adenosine prevented necrosis and favoured apoptosis. This effect was not a pecularity of BR-treatment, but was reproduced with high concentrations of all trans-retinoic acid (120 microM) and cyanide (20 mM). Glucose was also capable to suppress necrosis and to favour apoptosis of HL-60 cells, which had been treated with necrotic doses of BR and cyanide. Apoptosis eliminates unwanted cells without affecting the microenvironment, whereas necrosis causes severe inflammation of surrounding tissues due to spillage of cell fluids into the peri-cellular space. Thus, the monitoring and maintenance of cellular energy pools during therapeutic drug treatment may help to minimize nonspecific side effects and to improve attempted drug effects.
Grusch
M
M
Institute of Clinical Pathology, University of Vienna, Austria.
Polgar
D
D
Gfatter
S
S
Leuhuber
K
K
Huettenbrenner
S
S
Leisser
C
C
Fuhrmann
G
G
Kassie
F
F
Steinkellner
H
H
Smid
K
K
Peters
G J
GJ
Jayaram
H N
HN
Klepal
W
W
Szekeres
T
T
Knasmüller
S
S
Krupitza
G
G
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis / Q000502:physiology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D020552:Comet Assay; D004249:DNA Damage; D003838:Deoxyadenine Nucleotides / Q000032:analysis; D003845:Deoxycytosine Nucleotides / Q000032:analysis; D003854:Deoxyribonucleotides / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D009336:Necrosis; D009705:Nucleosides / Q000633:toxicity*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011190:Potassium Cyanide / Q000037:antagonists & inhibitors; D014212:Tretinoin / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001549:Benzamides; D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D003854:Deoxyribonucleotides; D004791:Enzyme Inhibitors; D009705:Nucleosides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C076145:3-(1-deoxyribofuranosyl)benzamide; C024107:2'-deoxycytidine 5'-triphosphate; D014212:Tretinoin; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D000241:Adenosine; C026600:2'-deoxyadenosine triphosphate; D011190:Potassium Cyanide