Digalloylresveratrol, a novel resveratrol analog inhibits the growth of human pancreatic cancer cells.
Digalloylresveratrol (DIG) is a recently synthesized substance aimed to combine the effects of the natural polyphenolic compounds gallic acid and resveratrol, which both are excellent free radical scavengers with anticancer activity. In this study, we investigated the effects of DIG in the human AsPC-1 and BxPC-3 pancreatic adenocarcinoma cell lines. Treatment with DIG dose-dependently attenuated cells in the S phase of the cell cycle and led to a significant depletion of the dATP pool in AsPC-1 cells. The incorporation of (14)C-cytidine into nascent DNA of tumor cells was significantly inhibited at all DIG concentrations due to inhibition of ribonucleotide reductase, a key enzyme of DNA synthesis in tumor cells. Furthermore, Erk1/2 became inactivated and moderated p38 phosphorylation reflecting increased replication stress. DIG also activated ATM and Chk2, and induced the phosphorylation and proteasomal degradation of the proto-oncogene Cdc25A, which contributed to cell cycle attenuation. Taken together, DIG is an excellent free radical scavenger, strongly inhibits RR in situ activity, cell cycle progression, and colony formation in AsPC-1 and BxPC-3 cells thus warranting further investigations.
Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Philipp
P
Saiko
Geraldine
G
Graser
Benedikt
B
Giessrigl
Marie-Thérèse
MT
Steinmann
Heike
H
Schuster
Andreas
A
Lackner
Michael
M
Grusch
Georg
G
Krupitza
Walter
W
Jaeger
Venkateswarlu
V
Somepalli
Trimurtulu
T
Golakoti
Monika
M
Fritzer-Szekeres
Thomas
T
Szekeres
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003562:Cytidine / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010851:Picrates / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; C000715470:MAS1 protein, human; D010851:Picrates; D000090063:Proto-Oncogene Mas; D013267:Stilbenes; C534866:digalloylresveratrol; D003562:Cytidine; D005707:Gallic Acid; D004247:DNA; C004931:1,1-diphenyl-2-picrylhydrazyl; D012264:Ribonucleotide Reductases; D020928:Mitogen-Activated Protein Kinases