Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells

Sibylle Madlener; Christoph Illmer; Zsuzsanna Horvath; Philipp Saiko; Annemarie Losert; Irene Herbacek; Michael Grusch; Howard L Elford; Georg Krupitza; Astrid Bernhaus; Monika Fritzer-Szekeres; Thomas Szekeres

doi:10.1016/j.canlet.2006.01.001

Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells

Cancer Lett. 2007 Jan 8;245(1-2):156-62. doi: 10.1016/j.canlet.2006.01.001. Epub 2006 Feb 20.

Authors

Sibylle Madlener¹, Christoph Illmer, Zsuzsanna Horvath, Philipp Saiko, Annemarie Losert, Irene Herbacek, Michael Grusch, Howard L Elford, Georg Krupitza, Astrid Bernhaus, Monika Fritzer-Szekeres, Thomas Szekeres

Affiliation

¹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

PMID: 16488533
DOI: 10.1016/j.canlet.2006.01.001

Abstract

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.

MeSH terms

Adenosine Triphosphate / metabolism
Apoptosis / drug effects
Benzamidines / chemistry
Benzamidines / pharmacology
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclooxygenase Inhibitors / pharmacology*
Cytidine Triphosphate / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Gallic Acid / chemistry
Gallic Acid / pharmacology*
Guanosine Triphosphate / metabolism
HL-60 Cells
Humans
Leukemia, Promyelocytic, Acute / enzymology
Leukemia, Promyelocytic, Acute / metabolism
Leukemia, Promyelocytic, Acute / pathology
Molecular Structure
Prostaglandin-Endoperoxide Synthases / metabolism*
Ribonucleotide Reductases / antagonists & inhibitors*
Ribonucleotide Reductases / metabolism
Thymine Nucleotides / metabolism

Substances

3,4,5-trihydroxybenzamidoxime
Benzamidines
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Thymine Nucleotides
Gallic Acid
Cytidine Triphosphate
Guanosine Triphosphate
Adenosine Triphosphate
Prostaglandin-Endoperoxide Synthases
Ribonucleotide Reductases
thymidine 5'-triphosphate