Biomedical subjects

Harukuni Tokuda

Publications and source records attributed to Harukuni Tokuda.

At least 73 records · Page 4Linked to original sources

PubMed2003

Cancer chemopreventive effects of oral feeding alpha-tocopherol on ultraviolet light B induced photocarcinogenesis of hairless mouse.

Ultraviolet light is the most common cause of skin cancers in humans and several effects of ultraviolet light B (UVB: 290-320 nm) are thought to contribute to skin photocarcinogenesis. The generation of free radicals and related oxidants produced by UVB exposure, result in photocarcinogenesis by directly damaging DNA. On the other side, activating of transcription factor, activator protein 1 (AP-1) induced by UVB exposure causes tumor promotion. alpha-tocopherol has two principal physiological activities and one is an antioxidant activity through which alpha-tocopherol protects unsaturated fatty acids, protein and DNA from oxidation. The other activity is to stabilize the structure of the biomembrane. In addition to these two activities, it has been recently established that alpha-tocopherol plays important roles in cell signal transduction. In course of these studies, we examined such effects of alpha-tocopherol on UVB induced skin photocarcinogenesis in hairless mice. These results indicate that oral feeding of alpha-tocopherol including diet exhibited a marked inhibitory effects on both tumor incidence and multiplicity in UVB induced mouse skin photocarcinogenesis.

Administration, Oral↗

PubMed2003

H-ras mutations at codon 61 or 13 in tumors initiated with a NO donor in mouse skin.

The tumor-initiating activity of nitric oxide (NO) in carcinogenesis was assessed using (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexenamide (NOR1), a synthetic NO donor. Topical application of NOR1 followed by 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment twice a week for 20 weeks resulted in the development of papillomas in mice. All of the papillomas examined contained H-ras mutations at codons 61 or 13. At codon 61, CAA-CTA and CAA-TTA mutations were seen in 42/46 and 1/46 of the papillomas, respectively. Three papillomas without a mutation at codon 61 were mutated at codon 13. A GGC-CGC mutation was found in two of these samples while the third possessed a GGC-GTC mutation. These results suggest that NO possesses tumor-initiating activity through a process that induces mutation in H-ras.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2003

Cancer preventive potential of trichothecenes from Trichothecium roseum.

Bioassay-guided separation of extracts from the culture broth and mycelium of the fungus Trichothecium roseum, aiming at the discovery for cancer preventive agents, resulted in the isolation of three new trichothecene sesquiterpenes, trichothecinols A-C (1-3) together with three known analogues, trichothecin (4), trichodermol (5) and trichothecolone (6). Compounds 1-6 exhibited remarkably potent inhibition against Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Further compound 1 strongly inhibited TPA-induced tumor promotion on mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) in two-stage carcinogenesis tests. These results suggest that compound 1 might be a valuable lead for further evaluation as a cancer preventive agent. In addition to their cancer preventive activity, compound 2 was found to show modest antifungal activity against Crypotcoccus albidus and Saccharomyces cerevisiae.

Animals↗

PubMed2003

The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.

Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CML), but remissions induced in advanced-phase CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Isolation, structural elucidation, and inhibitory effects of terpenoid and lipid constituents from sunflower pollen on Epstein-Barr virus early antigen induced by tumor promoter, TPA.

Eight fatty acid esters of triterpene alcohols (1-8), four free triterpene alcohols (9, 12, 17, and 18), four diterpene acids (19-22), two tocopherol-related compounds (23 and 24), four estolides (25-28), three syn-alkane-4,6-diols (29-31), one 1,3-dioxoalkanoic acid (32), and one aliphatic ketone (33), along with the mixture of free fatty acids, were isolated from the diethyl ether extract of the pollen grains of sunflower (Helianthus annuus). Among these compounds, 14 (2-8, 12, 23, 25-28, and 33) were new naturally occurring compounds, and their structures were determined on the basis of spectroscopic methods. Twenty-four terpenoids and lipids (1-4, 6-9, 12, and 19-33) and six free triterpene triols (10, 11, and 13-16), derived from their fatty acid esters (2, 3, and 5-8) by alkaline hydrolysis, were evaluated with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), in Raji cells, which is known to be a primary screening test for antitumor promoters. Among the 30 compounds tested, 21 compounds possessing a di- or a polycyclic ring system in the molecule (1-4, 6-16, and 19-24) showed potent inhibitory effects on EBV-EA induction (91-100% inhibition at 1 x 10(3) mol ratio/TPA).

Antigens, Viral↗

PubMed2003

Cancer chemopreventive activity of acridone alkaloids on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

Seventeen acridone alkaloids isolated from the Rutaceous plants were tested for their inhibitory activities against Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. Some prenylated acridones were found to have remarkably potent activities. 1,3-Dihydroxy-10-methyl-2,4-diprenylacridone (18) as synthesized according to these results in vitro, exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The result of the present investigation indicated that some of these acridone alkaloids may be potentially valuable cancer chemopreventive agents.

Acridines↗

PubMed2003

Antitumor agents 220. Antitumor-promoting effects of cimigenol and related compounds on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

Cimigenol (1) and 39 related compounds were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Structure-activity relationship analysis indicated that compound 1 showed the highest activity and also exhibited significant inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that 1 and the related compounds might be valuable anti-tumor promoters.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2003

Synthesis and anti-tumor-promoting activity of glycoglycerolipid analogues lacking the glycerol backbone.

Glycoglycerolipid analogues lacking the glycerol backbone were prepared through a lipase catalyzed transesterification of beta-D-galactosylethylene glycol. The inhibitory effect of the resultant isomeric hexanoates at the primary alcoholic positions, beta-D-galactosylethylene glycol itself and nonyl beta-D-galactopyranoside, was tested on Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells promoted by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), as a primary screening test for inhibitors of tumor promotion. All the compounds assayed were found to be less active than the reference 2-O-beta-D-galactopyranosylglycerol derivatives, of which they are simplified models, indicating that the anti-tumor-promoting activity is very closely related to the presence of a free hydroxymethylene group on the glycerol-like aglycone moiety.

Anticarcinogenic Agents↗

PubMed2003

Tumor initiating activity of Helicobacter pylori water extract on mouse skin carcinogenesis.

Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis, but responsible and detail mechanisms are insufficient by the absence of adequate data. To obtain direct evidence regarding the carcinogenicity of H. pylori, we investigated the initiating and promoting activity of H. pylori water extract (HPE) in two-stage mouse skin carcinogenesis model. HPE treatment, as an initiation, significantly enhanced tumor formation compared with control group. Moreover, HPE treatment increased production of 8-hydroxydeoxyguanosine in epidermal cells and HPE-initiated/TPA-promoted papillomas demonstrated a point mutation of the Ha-ras gene. These results suggest an initiating activity of HPE on two-stage mouse skin carcinogenesis.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

Isoflavonoids from Dalbergia olivari.

Two isoflavonoids, named olibergin A (1) and B (2) were isolated from the stem bark of Dalbergia oliveri (Leguminosae). Along with three previously known compounds, they are inhibitors of Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. Their structures were elucidated on the basis of spectroscopic analyses.

Antigens, Viral↗

PubMed2003

Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot.

Our previous studies identified the extract of Beta vulgaris (beetroot), commercially also known as betanin, as a potent cancer chemopreventive agent in both in vitro Epstein-Barr early antigen activation assay and in an in vivo two-stage mouse lung and skin carcinogenesis. To explore this issue further, we have now investigated its cancer chemopreventive potentials in three different chemical carcinogen initiation-promotion experimental tumor models in mice. Following tumor initiation with 390 nmol of 7,12-dimethylbenz(a)anthracene (DMBA) in 100 microl of acetone, the mouse skin tumor promotion with 3430 J/m(2) of ultraviolet light-B (UV-B) as well as splenomegaly was significantly inhibited by oral administration of 0.0025% betanin. At the same dose, betanin also afforded significant protection in the mouse skin cancer model following the topical application of 390 nmol of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) in 100 microl of acetone and promoted by topical administration of 1.7 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA). In the two-stage model of hepatocarcinogenesis in mice with N-nitrosodiethylamine (DEN, 30 mg/kg) as the initiator and phenobarbital as the promoter, oral administration of 0.0025% betanin also showed a very significant inhibition of both the incidence and multiplicity of the liver tumors. These findings along with our initial reports suggest that betanin which is a regularly consumed natural product colorant is an effective cancer chemopreventive agent in mice. The most interesting observation is that the cancer chemopreventive effect was exhibited at a very low dose used in the study and thus indicating that beetroot warrants more attention for possible human applications in the control of malignancy.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2003

Chemical constituents of Garcinia fusca: structure elucidation of eight new xanthones and their cancer chemopreventive activity.

We describe the isolation and spectrometric structure elucidation of eight new xanthones, fuscaxanthone A (1), B (2), C (3), D (4), E (5), F (6), G (7), and H (8), together with eight known xanthones from the stem bark of Garcinia fusca collected in Thailand. All the new xanthones were shown to have a terpenoid (prenyl and/or geranyl) side chain(s) in their molecules. We also present the results of a primary screening of the inhibitory effects of eight xanthones (9-16) isolated as major components of this plant on 12-O-tetradecanoylphorbol-13-acetate induced Epstein-Barr virus early antigen activation in Raji cells.

Antigens, Viral↗

PubMed2003

Chemical constituents of Calophyllum brasiliense. 2. Structure of three new coumarins and cancer chemopreventive activity of 4-substituted coumarins.

Continuing our search for cancer chemopreventive agents from natural sources, we examined constituents of the stem bark of Calophyllum brasiliense. Three new 4-substituted coumarins named brasimarins A (2), B (3), and C (4) were isolated and characterized, along with 11 known coumarins belonging to the calanolides or inophyllums. We also discuss the inhibitory effects of these coumarins on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.

Anticarcinogenic Agents↗

PubMed2003

Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities.

In a further study on the chemical constituents of Garcinia assigu, two new benzophenones corresponding to the 13-O-methyl ethers (1 and 2) of the known isogarcinol and garcinol, respectively, were isolated and characterized, along with known benzophenones (3-6). Inhibitory effects of the benzophenones isolated from this plant on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and their radical-scavenging ability against 1,1-diphenyl-2-picrylhydrazyl (DPPH) were demonstrated. The cyclized polyprenylbenzophenones (1-5) showed comparable or stronger potential cancer chemopreventive activity when compared to glycyrrhetic acid, a known anti-tumor promoter.

Anticarcinogenic Agents↗

PubMed2003

Absolute configuration of sesquiterpenes from Crossopetalum tonduzii and their inhibitory effects on Epstein-Barr virus early antigen activation in Raji cells.

Two new sesquiterpenoids (1 and 2) with a dihydro-beta-agarofuran skeleton were isolated from Crossopetalum tonduzii. Their structures were elucidated on the basis of spectral analysis, including homonuclear and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC, and HMBC). Their absolute configurations were determined by CD studies on 3, the benzoylated derivative of 1. Chemical correlations have allowed the absolute configurations of 4 and 5, two previously known dihydro-beta-agarofuran analogues, to be reported for the first time. Compounds 1, 2, and 5 showed strong antitumor-promoting effects on Epstein-Barr virus early antigen (EBV-EA) activation.

Acetylation↗

PubMed2003

Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barr virus activation.

A new triterpene acid, lucidenic acid P (1a), and two new triterpene acid methyl esters, methyl lucidenates P (1b) and Q (2b), were isolated and characterized from the fruiting body of the fungus Ganoderma lucidum. Their structures were elucidated on the basis of spectroscopic methods. In addition, eight known triterpene acids, lucidenic acids A (3a), C (4a), D(2) (5a), E(2) (6a), and F (7a) and ganoderic acids E (9a), F (10a), and T-Q (11a), and six known triterpene acid methyl esters, methyl lucidenates A (3b), D(2) (5b), E(2) (6b), F (7b), and L (8b) and methyl ganoderate F (10b), were isolated and identified from the fungus. All of the triterpenoids, with the exception of 7a, were evaluated with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, which is known to be a primary screening test for antitumor promoters. All of the compounds tested showed potent inhibitory effects on EBV-EA induction (96-100% inhibition at 1 x 10(3) mol ratio/TPA).

Antigens, Viral↗

PubMed2003

New cinnamylphenols from Dalbergia species with cancer chemopreventive activity.

Five new cinnamylphenols (1,3-diphenylpropenes), dalberatins A (1), B (2), C (3), D (4), and E (5), were isolated from plants of the Dalbergia species. They were characterized and tested for their inhibitory activities against Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. The cinnamylphenols were found to show remarkably potent activities. The result of the present investigation indicated that some of these cinnamylphenols might be valuable as potential cancer chemopreventive agents (anti-tumor promoters).

Anticarcinogenic Agents↗

PubMed2003

Sunpollenol and five other rearranged 3,4-seco-tirucallane-type triterpenoids from sunflower pollen and their inhibitory effects on Epstein-Barr virus activation.

Six new rearranged 3,4-seco-tirucallane-type triterpenoids (1-6) have been isolated from the diethyl ether extract of the pollen grains of sunflower (Helianthus annuus). These compounds were evaluated with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells. All of the compounds tested showed potent inhibitory effects on EBV-EA activation (97-100% inhibition at 1 x 10(3) mol ratio/TPA).

Antigens, Viral↗