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

Abstract

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.

Inedible mushrooms: a good source of biologically active substances

“…44 So far, these compounds have been shown to possess interesting biological activities, such as anti-inflammatory, 45,46 antimicrobial, 47,48 anti-HIV, 49 and DNA polymerase and DNA topoisomerase inhibitory activity. 50 Investigation on the methanolic extract of the Japanese inedible mushroom F. spraguei (Polyporaceae) led to the isolation of five lanostane-type triterpenoids: three new compounds named fomitopsins A ¶C (25)(26)(27), and two known compounds, quercinic acid C (28) and 3α-carboxyacetyl-12β-hydroxyquercinic acid (29) (Fig. 5).…”

“…58 Their antioxidant activities were defined as the amount of antioxidant necessary to decrease the initial DPPH radical concentration by 50% [IC 50 (µM)] as described in Table 8 and compared with those of known antioxidants, lascorbic acid, α-tocopherol, and BHA. According to Table 8, p-terphenyl possessing para-dihydroxyl groups at the central aromatic ring showed stronger antioxidative activities than those compounds with four substitution groups as 92 and 95.…”

“…Note: The nematode suspension was diluted with phosphate-buffered saline (1000 nematodes/mL) and incubated with the test compounds. LD 50 and LD 90 were evaluated after 18 h, counting the percentages of motile and dead nematodes under a dissection microscope. LD 90 = 90% lethal doses; LD 50 = 50% lethal doses.…”

“…Grifolin (1) strongly suppressed TNF-α production with 50% inhibitory concentration (IC 50 ) values of 3.98 µM, while the other compounds exhibited a weak and similar inhibitory activity. The finding suggested that the presence of the carboxylic group at C-1 in 6, 7 and 9, 10 decreased the inhibitory activity.…”

Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7

“…Poria cocos (also known as Wolfiporia extensa) is a medicinal mushroom in the Polyporaceae family that grows in pine trees and its sclerotium is widely used in traditional Asian medicine for its sedative, diuretic, digestive and tonic effects (6)(7)(8). Although the anticancer activity of polysaccharides extracted from P. cocos is associated with the stimulation of immune response and these polysaccharides significantly enhance immunopotentiation (9), triterpenes isolated from P. cocos have a direct inhibitory effect on cancer cells through a variety of mechanisms including inhibition of cell proliferation, induction of apoptosis and suppression of invasive behavior (10)(11)(12)(13)(14)(15)(16). However the effect of triterpenes from P. cocos against pancreatic cancer remains to be evaluated and the mechanism determined.…”