Inhibitory effects of low molecular weight polyphenolics from Inonotus obliquus on human DNA topoisomerase activity and cancer cell proliferation.

Abstract

Low molecular weight (LMW) polyphenolics containing a polyhydroxylated benzyl moiety are abundant in medicinal plants. In the present study, we report on the activities of seven LMW polyphenolics isolated from Inonotus obliquus, a medicinal mushroom. The isolated compounds included caffeic acid (CA), 3,4-dihydroxybenzalacetone (DBL), gallic acid, syringic acid, protocatechuic acid, 3,4-dihydroxybenzaldehyde and 2,5-dihydroxyterephthalic acid. We analyzed their inhibitory effects on DNA polymerase (pol) and DNA topoisomerase (topo), and their effects on human cancer cell growth. All isolated compounds inhibited human topo II activity; the most potent were DBL and CA, which contain a catechol propanoid moiety. CA and DBL inhibited the activity of human topo I, whereas other compounds had no effect. No compound modulated the activities of 11 mammalian pol species or other DNA metabolic enzymes, including T7 RNA polymerase, mouse IMP dehydrogenase (type II), T4 polynucleotide kinase and bovine deoxyribonuclease I. CA and DBL markedly suppressed the proliferation of human colon HCT116 carcinoma cells with an LD50 of 70.0 and 49.4 µM, respectively, and halted the cell cycle in the G2/M phase. The suppressive effect of these compounds on cancer cell growth correlated with their ability to inhibit topo II. These results suggest that CA- and DBL-dependent decreases in cell proliferation are due to the inhibition of cellular topo II. The mechanism of action of these catechol propanoid compounds and the implication for their use as anticancer agents are discussed.

• Authors: Isoko Kuriyama, Yuki Nakajima, Hiroshi Nishida, Tetsuya Konishi, Toshifumi Takeuchi, Fumio Sugawara, Hiromi Yoshida, Yoshiyuki Mizushina
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 8 Issue 2 Pg. 535-42 (Aug 2013) ISSN: 1791-3004 [Electronic] Greece
• PMID: 23799608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Polyphenols
• Topoisomerase Inhibitors
• DNA Polymerase I
• DNA Polymerase beta
• DNA Topoisomerases, Type I

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Basidiomycota (chemistry)
• Cattle
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Computers, Molecular
• DNA Polymerase I (metabolism)
• DNA Polymerase beta (metabolism)
• DNA Topoisomerases, Type I (metabolism)
• Enzyme Activation (drug effects)
• HCT116 Cells
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Molecular Weight
• Polyphenols (chemistry, pharmacology)
• Rats
• Topoisomerase Inhibitors (chemistry, pharmacology)