Harukuni Tokuda

Kanazawa University, Kanazawa, Ishikawa, Japan

Are you Harukuni Tokuda?

Claim your profile

Publications (381)1185.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Two jasmonate derivatives, glucosylcucurbic acid (1) and methyl glucosylcucurbate (2), were isolated from the MeOH extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels. These and their deglucosylated derivatives, cucurbic acid (3) and methyl cucurbate (4), were evaluated for their melanogenesis-inhibitory and cancer chemopreventive potencies. Compounds 1, 3, and 4 exhibited potent melanogenesis-inhibitory activities in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells. Western-blot analysis revealed that compounds 1 and 3 reduced the protein levels of MITF (=microphthalmia-associated transcription factor), tyrosinase, TRP-1 (=tyrosine-related protein 1), and TRP-2 mostly in a concentration-dependent manner. In addition, compound 1 exhibited inhibitory effects against EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, against TPA-induced inflammation in mice, and against skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.
    Chemistry & Biodiversity 04/2015; 12(4):547-58. DOI:10.1002/cbdv.201400424 · 1.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Three new oxidative metabolites of lycopenes, (erythro)-lycopene-5,6-diol, (threo)-lycopene-5,6-diol, and 1,16-dehydro-2,6-cyclolycopene-5-ol B, and four new oxidative metabolites of γ-carotenes, 2',6'-cyclo-γ-carotene-1',5'-diol A, 2',6'-cyclo-γ-carotene-1',5'-diol B, (erythro)-γ-carotene-5,6-diol, and (threo)-γ-carotene-5,6-diol, were isolated as minor components from the aril of gac, Momordica cochinchinensis. These structures were determined on the basis of spectroscopic data, and some of them were compared to the structures of synthetic samples. Furthermore, the oxidative metabolic conversion pathways of lycopene and γ-carotene were discussed.
    Journal of Agricultural and Food Chemistry 01/2015; 63(5). DOI:10.1021/jf505008d · 3.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (3), in which the C-1 ester group was replaced with an amide group, to improve chemical stability in vivo. Unfortunately, 3 exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10(-4) M. A conformational analysis and density functional theory calculations indicated that the stable conformation of 3 differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (1, 2) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10(-4) M, 3 may be an inactive control to identify the target proteins of aplogs.
    Bioscience Biotechnology and Biochemistry 01/2015; 79(6):1-8. DOI:10.1080/09168451.2014.1002452 · 1.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to produce a novel keto-carotenoid in Escherichia coli, we introduced the marine bacterial carotenoid ketolase gene (crtW) into pathway-engineered E. coli producing carotenoids of plant origin, which carried the lycopene biosynthesis genes (crtE, crtB, and crtI) from soil bacterium Pantoea ananatis and the liverwort Marchantia polymorpha genes that encode lycopene β-cyclase (MpLCYb), lycopene ε-cyclase (MpLCYe), and β-carotenoid hydroxylase (MpBHY). A novel keto-carotenoid (1) was produced by these carotenoid biosynthesis genes in E. coli along with α-echinenone, adonirubin, and adonixanthin. The structure of 1 was determined as (3S,6′R)-3-hydroxy-β,ε-caroten-4-one based on Uv–vis, MS, 1H NMR, and CD spectral data. This compound was named 4-ketozeinoxanthin and showed anti-tumor-promoting activity.
    Tetrahedron Letters 12/2014; 55(49). DOI:10.1016/j.tetlet.2014.10.033 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The MeOH extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels was investigated for its constituents, and fifteen oleanane-type triterpene acids and glycosides, two steroid glucosides, two pentane-2,4-diol glucosides, seven phenolic compounds, and three sugars, were isolated. The structures of five triterpene glycosides were elucidated on the basis of spectroscopic and chemical methods. Upon evaluation of the bioactivity of the isolated compounds, it was found that some or most of the compounds have potent or moderate inhibitory activities against the following: melanogenesis in B16 melanoma cells induced by α-melanocyte-stimulating hormone (α-MSH); generation of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, against Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-teradecanoylphorbol 13-acetate (TPA) in Raji cells; t TPA-induced inflammation in mice, and proliferation of one or more of HL-60, A549, AZ521, and SK-BR-3 human cancer cell lines, respectively. Western blot analysis established that paradoxoside E inhibits melanogenesis by regulation of expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1 (TRP-1) and TRP-2. In addition, tieghemelin A was demonstrated to exhibit cytotoxic activity against A549 cells (IC50 13.5 μM) mainly due to induction of apoptosis by flow cytometry. The extract of defatted shea kernels and its constituents may be, therefore, valuable as potential antioxidant, anti-inflammatory, skin-whitening, chemopreventive, and anticancer agents.
    Phytochemistry 12/2014; 108. DOI:10.1016/j.phytochem.2014.09.017 · 3.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.
    Tetrahedron Letters 11/2014; 55(47). DOI:10.1016/j.tetlet.2014.10.038 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nine limonoids, 1–9, one apocarotenoid, 11, one alkaloid, 12, and one steroid, 13, from the leaf extract; and one triterpenoid, 10, five steroids, 14–18, and two flavonoids, 19 and 20, from the bark extract of Melia azedarach L. (Chinaberry tree; Meliaceae) were isolated. Among these compounds, three compounds, 4–6, were new, and their structures were established as 3-deacetyl-28-oxosalannolactone, 3-deacetyl-28-oxosalanninolide, and 3-deacetyl-17-defurano-17,28-dioxosalannin, respectively, on the basis of extensive spectroscopic analyses and comparison with literature data. All of the isolated compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. 3-Deacetyl-4′-demethyl-28-oxosalannin (3) against HL60 and AZ521 cells, and methyl kulonate (10) against HL60 cells exhibited potent cytotoxicities with IC50 values in the range of 2.8–5.8 μM. In addition, upon evaluation of compounds 1–13 against production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), seven, i.e., trichilinin B (1), 4, ohchinin (7), 23-hydroxyohchininolide (8), 21-hydroxyisoohchininolide (9), 10, and methyl indole 3-carboxylate (12), inhibited production of NO with IC50 values in the range of 4.6–87.3 μM with no, or almost no, toxicity to the cells (IC50 93.2–100 μM). Western blot analysis revealed that compound 7 reduced the expression levels of the inducible NO synthase (iNOS) and COX-2 proteins in a concentration-dependent manner. Furthermore, compounds 5, 6, 13, and 18–20 exhibited potent inhibitory effects (IC50 299–381 molar ratio/32 pmol TPA) against EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cell line.
    Chemistry & Biodiversity 08/2014; 11(8). DOI:10.1002/cbdv.201400190 · 1.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemoprevention of cancers.
    Journal of Computer-Aided Molecular Design 05/2014; 28(6). DOI:10.1007/s10822-014-9748-9 · 2.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Two of each semisynthetic lanostane- and cycloartane-type triterpenes with a cyano-enone functionality, i.e., 13 and 18, and 23 and 28, respectively, sixteen of their synthetic intermediates, 9–12, 14–17, 19–22, and 24–27, along with seven semisynthetic oxygenated triterpene acetates, 29–35, and eight natural hydroxy triterpenes, 1–8, were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. One natural triterpene, 8, and ten semisynthetic triterpenes, 9, 13, 15, 18, 23, 25, 28, 29, 32, and 33, exhibited potent cytotoxicities against one or more cell lines with IC50 values in the range of 1.4–9.9 μM. Two lanostane-type triterpenes with a cyano-enone functionality, 3-oxolanosta-1,8,24-triene-2-carbonitrile (13) and 3-oxolanosta-1,8-diene-2-carbonitrile (18), induced apoptosis in HL60 cells, as observed by membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 13 and 18 significantly reduced procaspases-3, -8, and -9, and increased cleaved caspases-3, -8, and -9. These findings indicated that compounds 13 and 18 induced apoptosis in HL60 cells via both the mitochondrial and the death receptor-mediated pathways. In addition, upon evaluation of the inhibitory effects on EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, seven natural triterpenes, 1–6 and 8, and ten semisynthetic triterpenes, 9, 10, 14, 15, 19, 20, 24, 25, 29, and 30, exhibited inhibitory effects which were higher than that of β-carotene, a vitamin A precursor studied widely in cancer-chemoprevention animal models.
    Chemistry & Biodiversity 04/2014; 11(4). DOI:10.1002/cbdv.201300395 · 1.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Seventeen limonoids (tetranortriterpenoids), 1–17, including three new compounds, i.e., 17-defurano-17-(2,5-dihydro-2-oxofuran-3-yl)-28-deoxonimbolide (14), 17-defurano-17-(2ξ-2,5-dihydro-2-hydroxy-5-oxofuran-3-yl)-28-deoxonimbolide (15), and 17-defurano-17-(5ξ-2,5-dihydro-5-hydroxy-2-oxofuran-3-yl)-2′,3′-dehydrosalannol (17), were isolated from an EtOH extract of the leaf of neem (Azadirachta indica). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, seven compounds, i.e., 1–3, 12, 13, 15, and 16, exhibited potent cytotoxicities with IC50 values in the range of 0.1–9.9 μM against one or more cell lines. Among these compounds, cytotoxicity of nimonol (1; IC50 2.8 μM) against HL60 cells was demonstrated to be mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that compound 1 induced apoptosis via both the mitochondrial and death receptor-mediated pathways in HL60 cells. In addition, when compounds 1–17 were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α-melanocyte-stimulating hormone (α-MSH), seven compounds, 1, 2, 4–6, 15, and 16, exhibited inhibitory activities with 31–94% reduction of melanin content at 10 μM concentration with no or low toxicity to the cells (82–112% of cell viability at 10 μM). All 17 compounds were further evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.
    Chemistry & Biodiversity 03/2014; 11(3). DOI:10.1002/cbdv.201300348 · 1.80 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3-b]thiophene-4,9-dione was developed. This method employed Sonogashira coupling and tandem addition-elimination/intramolecular cyclization, and it enabled the preparation of versatile heterocycle-fused naphthoquinones from one substrate.
    Chemical & pharmaceutical bulletin 11/2013; 61(6):648-654. DOI:10.1002/chin.201347074 · 1.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new flavonoid glycoside, chrysin 6-C-β-rutinoside (chrysin α-L-rhamnopyranosyl-(1→6)-C-β-glucopyranoside; 2), and two new triterpene glycosides, (31R)-31-O-methylpassiflorine (7) and (31S)-31-O-methylpassiflorine (8), along with 14 known glycosides, including three flavonoid glycosides, 1, 3, and 4, six triterpene glycosides, 5, 6, and 9-12, three cyano glycosides, 13-15, and two other glycosides, 16 and 17, were isolated from a MeOH extract of the leaves of Passiflora edulis (passion flower; Passifloraceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of compounds 1-17 against the melanogenesis in the B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, isoorientin (1), 2, and (6S,9R)-roseoside (17), exhibited inhibitory effects with 37.3-47.2% reduction of melanin content with no, or almost no, toxicity to the cells (90.8-100.2% cell viability) at 100 μM. Western blot analysis showed that compound 2 reduced the protein levels of MITF, TRP-1, and tyrosinase, in a concentration-dependent manner while exerted almost no influence on the level of TRP-2, suggesting that this compound inhibits melanogenesis on the α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of TRP-1 and tyrosinase. In addition, compounds 1-17 were evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.
    Chemistry & Biodiversity 10/2013; 10(10):1851-1865. DOI:10.1002/cbdv.201300181 · 1.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aqueous extract of Peltophorum pterocarpum (Fabaceae) wood exhibited potent inhibitory effects against EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and against melanogenesis in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells, as well as potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity. Two phenolic acid derivatives, bergenin (1) and gallic acid (2), were isolated from the ethyl acetate (AcOEt)-soluble fraction obtained from the extract. Compound 1 exhibited potent inhibitory effect against EBV-EA activation and against skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Both compounds 1 and 2 exhibited melanogenesis-inhibitory activities in α-MSH-stimulated B16 melanoma cells, and, in addition, compound 2 showed strong DPPH radical-scavenging activity.
    Chemistry & Biodiversity 10/2013; 10(10):1866-1875. DOI:10.1002/cbdv.201300182 · 1.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity, bound to and activated protein kinase Cδ (PKCδ), that is involved in tumor suppression and apoptosis. To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we synthesized 27-methyl and 27-methoxy derivatives that differed in the ability to activate PKCδ. Activators of PKCδ like aplog-1 and 27-(R)-Me-aplog-1 strongly inhibited the growth of several cancer cell lines. On the other hand, 27-(S)-Me-aplog-1 and 27-O-Me-aplog-1 without the ability to activate PKCδ, exhibited only weak growth inhibitory activity against these cell lines. These results suggest indirectly that the activation of PKCδ might be involved in the anti-proliferative activity of aplog-1 against aplog-sensitive cancer cell lines.
    Tetrahedron 09/2013; 69(36):7636-7645. DOI:10.1016/j.tet.2013.02.008 · 2.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin.
    European Journal of Medicinal Chemistry 08/2013; 69C:115-124. DOI:10.1016/j.ejmech.2013.07.049 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nine phenolic compounds, including two phenolic carboxylic acids, 1 and 2, seven hydrolyzable tannins, 3-9, eight triterpenoids, including four oleanane-type triterpene acids, 10-13, and four of their glucosides, 14-17, isolated from a MeOH extract of the gall of Terminalia chebula Retz. (myrobalan tree; Combretaceae), were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells induced by α-melanocyte-stimulating hormone (α-MSH), against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells, and against TPA-induced inflammation in mice. Their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities and cytotoxic activities against four human cancer cell lines were also evaluated. Compounds 6-9 and 12 exhibited potent inhibitory activities against melanogenesis (39.3-66.3% melanin content) with low toxicity to the cells (74.5-105.9% cell viability) at a concentration of 10 μM. Western-blot analysis revealed that isoterchebulin (8) reduced the protein levels of MITF (=microphtalmia-associated transcription factor), tyrosinase, and TRP-1 (=tyrosine-related protein 1), mostly in a concentration-dependent manner. Eight triterpenoids, 10-17, showed potent inhibitory effects on EBV-EA induction with the IC50 values in the range of 269-363 mol ratio/32 pmol TPA, while these compounds exhibited no DPPH scavenging activities (IC50 >100 μM). On the other hand, the nine phenolic compounds, 1-9, exhibited potent radical-scavenging activities (IC50 1.4-10.9 μM) with weak inhibitory effects on EBV-EA induction (IC50 460-518 mol ratio/32 pmol TPA). The tannin 6 and seven triterpenoids, 10-16, have been shown to inhibit TPA-induced inflammation (1 μg/ear) in mice with the ID50 values in the range of 0.06-0.33 μmol/ear. Arjungenin (10) exhibited inhibitory effect on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and with TPA as promoter. Compounds 1, 2, 4, 5, 7-9, 12, and 13, against HL60 cell line, compounds 1 and 4, against AZ521 cell line, and compounds 1, 11, and 12, against SK-BR-3 cell line, showed moderate cytotoxic activities (IC50 13.9-73.2 μM).
    Chemistry & Biodiversity 08/2013; 10(8):1448-63. DOI:10.1002/cbdv.201300149 · 1.80 Impact Factor
  • Planta Medica 07/2013; 79(10). DOI:10.1055/s-0033-1348683 · 2.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Extract of Lentinula edodes mycelia (LEM) is currently utilized as an oral biological response modifier (BRM) medicine for cancer patients. However, its effectiveness for breast cancer patients with postoperative adjuvant hormone therapy has not yet been scientifically verified. In this study, we investigated the influence of LEM on the quality of life (QOL) and immune response in breast cancer patients undergoing postoperative adjuvant hormone therapy. Twenty patients were studied in total. They received only hormone therapy in the first 4 weeks followed by hormone therapy and LEM during the next 8 weeks. Laboratory tests, QOL score and peripheral blood cytokine production levels were evaluated during the study period. No changes in QOL or cytokines were noted after the first 4 weeks. In contrast, during the following combined therapy period, improvements were noted in QOL and cytokine levels. Although a future large-scale investigation is necessary to confirm these results, these data suggest that the concomitant use of LEM with postoperative adjuvant hormone therapy improves the QOL and immune function of patients.
    Asian Pacific journal of cancer prevention: APJCP 06/2013; 14(6):3469-72. DOI:10.7314/APJCP.2013.14.6.3469 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy-1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.
    Anti-cancer agents in medicinal chemistry 06/2013; DOI:10.2174/18715206113139990096 · 2.94 Impact Factor

Publication Stats

8k Citations
1,185.40 Total Impact Points

Institutions

  • 2009–2015
    • Kanazawa University
      • Graduate School of Medical Sciences
      Kanazawa, Ishikawa, Japan
  • 1991–2014
    • Kyoto Prefectural University of Medicine
      • • Division of Biochemistry and Molecular Biology
      • • Graduate School of Medical Science
      Kioto, Kyōto, Japan
  • 2013
    • Kinki University
      Ōsaka, Ōsaka, Japan
  • 2012–2013
    • University of Szeged
      • Department of Medical Microbiology and Immunbiology
      Szeged, Csongrad megye, Hungary
  • 2011
    • Howard University
      • Department of Pharmaceutical Science
      Washington, WV, United States
  • 2008–2011
    • Takasaki University of Commerce
      Takasaki, Gunma Prefecture, Japan
  • 2010
    • Nagoya City University
      • Faculty of Pharmaceutical Sciences
      Nagoya, Aichi, Japan
  • 2000–2010
    • Hiroshima University
      • Faculty of Integrated Arts and Sciences
      Hirosima, Hiroshima, Japan
    • Meijo University
      • Faculty of Pharmacy
      Nagoya, Aichi, Japan
  • 1983–2010
    • Kyoto University
      • • Division of Applied Life Sciences
      • • Division of Pharmaceutical Sciences
      • • Department of Microbiology
      Kioto, Kyōto, Japan
  • 2006–2008
    • Nihon University
      • College of Science and Technology
      Edo, Tōkyō, Japan
  • 2001–2008
    • University of Milan
      • Department of Chemistry, Biochemistry and Biotechnologies for Medical Sciences
      Milano, Lombardy, Italy
  • 1999–2008
    • University of North Carolina at Chapel Hill
      • Division of Chemical Biology and Medicinal Chemistry
      Chapel Hill, NC, United States
  • 2004
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
  • 2002–2004
    • Kobe Pharmaceutical University
      Kōbe, Hyōgo, Japan
    • ICHIMARU PHARCOS Co., Ltd.
      Gihu, Gifu, Japan
  • 2000–2004
    • Kansai University
      Suika, Ōsaka, Japan
  • 2003
    • Toho University
      Edo, Tōkyō, Japan
  • 2001–2003
    • Osaka University of Pharmaceutical Sciences
      • Department of Medicinal Chemistry
      Ōsaka, Ōsaka, Japan
  • 2000–2003
    • Okayama University
      • Faculty of Pharmaceutical Science
      Okayama, Okayama, Japan
  • 1990–1999
    • Kyoto Pharmaceutical University
      Kioto, Kyōto, Japan
  • 1993
    • Setsunan University
      • Faculty of Pharmaceutical Sciences
      Ōsaka, Ōsaka, Japan
  • 1992
    • Kagoshima University
      Kagosima, Kagoshima, Japan