A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane‐type triterpene acids from Poria cocos

• Published in: Cancer science Vol. 95; no. 4; pp. 354 - 360
• Main Authors: Mizushina, Yoshiyuki, Akihisa, Toshihiro, Ukiya, Motohiko, Murakami, Chikako, Kuriyama, Isoko, Xu, Xianai, Yoshida, Hiromi, Sakaguchi, Kengo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2004; Blackwell; John Wiley & Sons, Inc
• Subjects: Acids; Animals; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Biological and medical sciences; Calf thymus; Cattle; Cell cycle; Cell Line, Tumor - drug effects; Cell Line, Tumor - enzymology; Deoxyribonucleic acid; DNA; DNA - drug effects; DNA - metabolism; DNA Fragmentation - drug effects; DNA nucleotidylexotransferase; DNA Nucleotidylexotransferase - antagonists & inhibitors; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA topoisomerase inhibitors; DNA-directed DNA polymerase; DNA-directed RNA polymerase; Drug Screening Assays, Antitumor; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; G1 phase; G1 Phase - drug effects; Gastric cancer; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; Human immunodeficiency virus; Humans; Mammals; Medical sciences; Medicinal plants; Molecular Structure; Nucleic Acid Synthesis Inhibitors; Plant Epidermis - chemistry; Polynucleotide kinase; Polyporales - chemistry; Poria cocos; Rats; RNA-directed DNA polymerase; Stomach Neoplasms - pathology; Structure-Activity Relationship; Substrate Specificity; Topoisomerase II Inhibitors; Triterpenes - chemistry; Triterpenes - isolation & purification; Triterpenes - pharmacology; Tumors; Inhibitor; Isomerases; Cancerology; Enzyme; DNA topoisomerase; Triterpene
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2004.tb03215.x

Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostanetype triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC50=4.6 μM), while the compound moderately inhibited the activities of DNA polymerases α, β, γ, δ, ɛ, η, iota;, κ and λ only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC50=37.5 μM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (α‐like polymerase) or II (βlike polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type‐1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonu‐clease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II‐preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD50 values were 63.6 and 38.4 μM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.