Cytotoxicity of p-tyrosol and its derivatives may correlate with the inhibition of DNA replication initiation.
p-Tyrosol is a phenolic compound present in different dietary sources that can exert mild antioxidant properties based on in vitro and in vivo studies. In our study, two p-tyrosol derivatives (p-tyrosyl gallate and p-tyrosyl acetate) were synthesized and compared together with p-tyrosol and gallic acid for their cytotoxic activities on human cancer cells. p-Tyrosyl gallate had the most potent cytotoxicity and the major cytotoxic mechanism of its action was studied. We found that in HeLa cells, p-tyrosyl gallate can effectively induce cell cycle arrest during S phase and inhibited in vitro simian virus (SV40 DNA) replication. In addition, p-tyrosyl gallate can inhibit three important functional replication proteins (topoisomerase I, RPA and pol alpha-primase), especially pol alpha-primase. These results suggest that p-tyrosyl gallate-induced cell cycle arrest during S phase correlates with the inhibition of DNA replication. Pol alpha-primase may be the main target molecule. Taken together, we suggest that p-tyrosyl gallate is a strong anticancer drug candidate that warrants further investigation.
Ahn
Eun-Young
EY
Biohealth Product Research Center, Inje University, Kimhae 621-749, Korea.
Jiang
Yahong
Y
Zhang
Yanjun
Y
Son
Eun Mi
EM
You
Song
S
Kang
Shin-Won
SW
Park
Jang-Su
JS
Jung
Jee H
JH
Lee
Burm-Jong
BJ
Kim
Dong-Kyoo
DK
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D004261:DNA Replication / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013539:Simian virus 40 / Q000187:drug effects
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; C527571:p-tyrosyl acetate; C527570:p-tyrosyl gallate; C011867:4-hydroxyphenylethanol; D019915:DNA Primase; C116932:DNA polymerase alpha-primase; D004256:DNA Polymerase I; D010626:Phenylethyl Alcohol