Inhibitory Effects of Lanostane-Type Triterpene Acids, the Components of &lt;i&gt;Poria cocos&lt;/i&gt;, on Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in Two-Stage Carcinogenesis in Mouse Skin

Kaminaga, Tomohiro; Yasukawa, Ken; Kanno, Hiroshi; Tai, Takaaki; Nunoura, Yoshiki; Takido, Michio

doi:10.1159/000227592

Cited by 72 publications

(65 citation statements)

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“…We also analyzed the kinetics of compound 5, and obtained similar results (data not shown). In the kinetic analysis, poly(dA)/oligo(dT) [12][13][14][15][16][17][18] and dTTP were used as the DNA template-primer and nucleotide substrate, respectively. Double-reciprocal plots of the results show that inhibition of pol α activity by compound 6 was noncompetitive with the DNA template and the nucleotide substrate.…”

Section: Resultsmentioning

confidence: 99%

“…Similar results were observed with compound 5: the pol α inhibition was non-competitive with both DNA template-primer and dTTP, but the pol β inhibition was competitive with both DNA template-primer and dTTP. When activated DNA was used as the template-primer DNA instead of synthesized DNA (i.e., poly(dA)/oligo(dT) [12][13][14][15][16][17][18] ), the inhibitory modes of the compounds were unchanged (data not shown). The triterpene acids may interact with or affect both of the binding sites on pol β, thereby decreasing its affinity for the DNA template and substrate, whereas they may bind or interact with a domain distinct from the template or substrate binding sites on pol α.…”

Section: Resultsmentioning

confidence: 99%

“…Activities of DNA polymerases were measured by the methods described previously. 24,25) The substrates of DNA polymerases used were poly(dA)/oligo(dT) [12][13][14][15][16][17][18] and dTTP as template-primer DNA and nucleotide substrate, respectively. One unit of each DNA polymerase activity was defined as the amount of enzyme that catalyzes the incorporation of 1 nmol of deoxyribonucleotide triphosphate (i.e., dTTP) into the synthetic template-primers (i.e., poly(dA)/oligo(dT) [12][13][14][15][16][17][18] , A/T=2/1) in 60 min at 37°C under the normal reaction conditions for each of the enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…Several of the lanostane-type triterpene acids were revealed to possess potent inhibitory effects on tumor cell growth. 11,12) On the other hand, some triterpene compounds are potent inhibitors of the DNA polymerases. 13,14) We, therefore, suspected that the medicinal components might have such activity.…”

mentioning

confidence: 99%

“…Therefore, information concerning the structural characteristics of these inhibitors may provide valuable insight for the design of new anti-cancer agents. [12][13][14][15][16][17][18] were purchased from Amersham Biosciences (Buckinghamshire, UK). Supercoiled pUC19 plasmid DNA was obtained from TaKaRa (Tokyo).…”

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

et al. 2004

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2004

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Polyporenic acid C induces caspase‐8‐mediated apoptosis in human lung cancer A549 cells

Ling

Zhou

Jia

et al. 2008

Molecular Carcinogenesis

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Lung cancer continues to be the leading cause of cancer-related mortality worldwide. This warrants the search for new and effective agents against lung cancer. We and others have recently shown that lanostane-type triterpenoids isolated from the fungal species Poria cocos (P. cocos) can inhibit cancer growth. However, the mechanisms responsible for the anticancer effects of these triterpenoids remain unclear. In this study, we investigated the effect of polyporenic acid C (PPAC), a lanostane-type triterpenoid from P. cocos, on the growth of A549 nonsmall cell lung cancer cells (NSCLC). The results demonstrate that PPAC significantly reduced cell proliferation via induction of apoptosis as evidenced by sub-G1 analysis, annexin V-FITC staining, and increase in cleavage of procaspase-8, -3, and poly(ADP-ribose)-polymerase (PARP). However, unlike our previously reported lanostane-type triterpenoid, pachymic acid, treatment of cells with PPAC was not accompanied by disruption of mitochondrial membrane potential and increase in cleavage of procaspase-9. Further, PPC-induced apoptosis was inhibited by caspase-8 and pan caspase inhibitors but not by a caspase-9 inhibitor. Taken together, the results suggest that PPAC induces apoptosis through the death receptor-mediated apoptotic pathway where the activation of caspase-8 leads to the direct cleavage of execution caspases without the involvement of the mitochondria. Furthermore, suppressed PI3-kinase/Akt signal pathway and enhanced p53 activation after PPAC treatment suggests this to be an additional mechanism for apoptosis induction. Together, these results encourage further studies of PPAC as a promising candidate for lung cancer therapy.

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Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells

Ling

Jia

Yao-chun

et al. 2009

Molecular Carcinogenesis

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Aberrant arachidonic acid (AA) metabolism has been involved in inflammation and carcinogenesis. The key enzymes in AA metabolism such as cytosolic phospholipase A2 (cPLA 2 ) and cyclooxygenase-2 (COX-2) have been implicated in the development and progression of many human cancers, including lung cancer. Hence, the blockade of these enzymes may suppress promotion and survival of human cancer cells. We and others have shown that a natural triterpenoid, pachymic acid (PA), can exhibit antiinflammatory and anticancer properties; however, its potential mechanism has not been fully clarified. In this study, we examined the effect of PA on the proliferation of human nonsmall cell lung cancer A549 cells. Furthermore, we investigated the influences of nontoxic levels of PA on AA metabolism. Additionally, the cellular events and signal transduction pathways influenced by PA were also examined. Our results showed that PA (1) inhibited anchorage-dependent and -independent A549 growth in a concentrationdependent manner, (2) induced apoptosis and disrupted mitochondrial membrane potential in A549 cells, and at nonlethal levels, (3) decreased IL-1b-induced activation of cPLA 2 and COX-2, (4) suppressed IL-1b-induced activation of mitogen-activated protein kinases (MAPKs), and (5) inhibited IL-1b-stimulated nuclear factor kappa B (NF-kB) signaling pathways. We speculate that inhibition of AA metabolism by PA is mediated in part by its inhibition of MAPKs and NF-kB signaling pathways. Our study reveals that, apart from its cytotoxic effect, PA has the chemopreventive potential by reducing production of eicosanoids from AA metabolism.

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Inhibitory Effects of Lanostane-Type Triterpene Acids, the Components of <i>Poria cocos</i>, on Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in Two-Stage Carcinogenesis in Mouse Skin

Cited by 72 publications

References 10 publications

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

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

Polyporenic acid C induces caspase‐8‐mediated apoptosis in human lung cancer A549 cells

Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells

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