Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells.
Gallic acid (GA) is a naturally occurring polyhydroxyphenolic compound and an excellent free radical scavenger. In this study, we examined its cytotoxic and biochemical effects on the human HL-60 promyelocytic leukemia cell line. GA caused a significant imbalance of deoxynucleosidetriphosphate (dNTP) pool sizes, indicating ribonucleotide reductase inhibition. Moreover, GA induced dose-dependent apoptosis in HL-60 cells (80microM GA led to the induction of apoptosis in 39% of cells) and attenuated progression from G0/G1 to the S phase of the cell cycle (60microM GA doubled the number of cells in G0/G1 phase from 22 to 44% when compared to untreated controls). We further determined IC(50) values of 3.5 and 4.4nM for the inhibition of cyclooxygenases I and II, respectively. When cells were simultaneously treated with GA and trimidox, another inhibitor of RR, highly synergistic growth inhibitory effects could be observed. Taken together, we identified novel biochemical effects of GA which could be the basis for further preclinical and in vivo studies.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Sibylle
S
Madlener
Christoph
C
Illmer
Zsuzsanna
Z
Horvath
Philipp
P
Saiko
Annemarie
A
Losert
Irene
I
Herbacek
Michael
M
Grusch
Howard L
HL
Elford
Georg
G
Krupitza
Astrid
A
Bernhaus
Monika
M
Fritzer-Szekeres
Thomas
T
Szekeres
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005707:Gallic Acid / Q000737:chemistry / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism
C074761:3,4,5-trihydroxybenzamidoxime; D001550:Benzamidines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D013942:Thymine Nucleotides; D005707:Gallic Acid; D003570:Cytidine Triphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D011451:Prostaglandin-Endoperoxide Synthases; D012264:Ribonucleotide Reductases; C024157:thymidine 5'-triphosphate