A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos.
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 lanostane-type 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 (IC(50) = 4.6 microM), while the compound moderately inhibited the activities of DNA polymerases alpha, beta, gamma, delta, epsilon, eta, iota, kappa and lambda only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC(50) = 37.5 microM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (alpha-like polymerase) or II (beta-like 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 T 7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonuclease 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 LD(50) values were 63.6 and 38.4 microM, 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.
Mizushina
Yoshiyuki
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science and High Technology Research Center, Kobe-Gakuin University, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
Akihisa
Toshihiro
T
Ukiya
Motohiko
M
Murakami
Chikako
C
Kuriyama
Isoko
I
Xu
Xianai
X
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D008322:Mammals; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D019441:Plant Epidermis / Q000737:chemistry*; D020072:Polyporales / Q000737:chemistry*; D051381:Rats; D013274:Stomach Neoplasms / Q000473:pathology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes; C487640:dehydroebriconic acid; C487641:dehydrotrametenonic acid; D004247:DNA; D004253:DNA Nucleotidylexotransferase; D054303:HIV Reverse Transcriptase