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Papers - Arai, Midori

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Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium

Utpal K. Karmakar, Naoki Ishikawa, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY (PERGAMON-ELSEVIER SCIENCE LTD) 23 ( 15 ) 4746 - 4754 2015.08

Accepted, ISSN 0968-0896

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11 alpha, 13-dihydroxanthinin (2) and 11 alpha, 13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 mu M, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 mu M. (C) 2015 Elsevier Ltd. All rights reserved.

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Boehmenan, a lignan from Hibiscus ficulneus, showed Wnt signal inhibitory activity

Takumi Shono, Naoki Ishikawa, Kazufumi Toume, Midori A. Arai, Firoj Ahmed, Samir K. Sadhu, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 25 ( 14 ) 2735 - 2738 2015.07

Accepted, ISSN 0960-894X

The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell-based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 mu M, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt-independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear b-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing beta-catenin levels. (C) 2015 Elsevier Ltd. All rights reserved.

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9-Hydroxycanthin-6-one, a beta-Carboline Alkaloid from Eurycoma longifolia, Is the First Wnt Signal Inhibitor through Activation of Glycogen Synthase Kinase 3 beta without Depending on Casein Kinase 1 alpha

Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Takamasa Mizoguchi, Motoyuki Itoh, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 78 ( 5 ) 1139 - 1146 2015.05

Accepted, ISSN 0163-3864

Wnt signaling regulates various processes such as cell proliferation, differentiation, and embryo development. However, numerous diseases have been attributed to the aberrant transduction of Wnt signaling. We screened a plant extract library targeting TCF/beta-catenin transcriptional modulating activity with a cell-based luciferase assay. Activity-guided fractionation of the MeOH extract of the E. longifolia root led to the isolation of 9-hydroxycanthin-6-one (1). Compound 1 exhibited TCF/beta-catenin inhibitory activity. Compound 1 decreased the expression of Wnt signal target genes, mitf and zic2a, in zebrafish embryos. Treatment of SW480 cells with 1 decreased beta-catenin and increased phosphorylated beta-catenin (Ser 33, 37, Tyr 41) protein levels. The degradation of beta-catenin by 1 was suppressed by GSK3 beta-siRNA, while compound 1 decreased beta-catenin even in the presence of CK1 alpha-siRNA. These results suggest that 1 inhibits Wnt signaling through the activation of GSK3 beta independent of CK1 alpha.

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Prenylated Flavonoids and Resveratrol Derivatives Isolated from Artocarpus communis with the Ability to Overcome TRAIL Resistance (vol 78, pg 103, 2015)

Toume, Kazufumi, Habu, Tadashi, Arai, Midori A., Koyano, Takashi, Kowithayakorn, Thaworn, Ishibashi, Masami

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 78 ( 4 ) 968 - 968 2015.04

Accepted, ISSN 0163-3864

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Scopadulciol, Isolated from Scoparia dulcis, Induces beta-Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells

Rolly G. Fuentes, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 78 ( 4 ) 864 - 872 2015.04

Accepted, ISSN 0163-3864

Scopadulciol (1), a scopadulan-type diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with 1 decreased beta-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of beta-catenin induced by 1. The 1-induced degradation of beta-catenin was also abrogated in the presence of pifithrin-alpha, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound 1 also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that 1 induced the p53- and proteasome-dependent degradation of beta-catenin, which resulted in the inhibition of TCF/beta-catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL.

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Calotropis giganteaからのノッチシグナル伝達経路阻害剤の探索

米山達朗, 荒井緑, 小柳津和音, 岡本隆一, Sadhu Samir K., Ahmed Firoj, 石橋正己

日本薬学会年会要旨集 ((公社)日本薬学会) 135年会 ( 2 ) 226 - 226 2015.03

ISSN 0918-9823

Limonoids with Wnt signal inhibitory activity isolated from the fruits of Azadirachta excelsa

Rolly G. Fuentes, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

PHYTOCHEMISTRY LETTERS (ELSEVIER SCIENCE BV) 11 280 - 285 2015.03

Accepted, ISSN 1874-3900

The Wnt signal regulates various biological processes, and its aberrant activation is associated with the development of diseases. Thus, inhibiting the Wnt signal provides a promising strategy to treat these diseases. Our cell-based luciferase assay system, which targets the Wnt signal (TOP assay), revealed that Azadirachta excelsa inhibited the Wnt signal. The activity-guided isolation of the MeOH fruit extract of A. excelsa provided one new (1) and seven known (2-8) limonoids. Their structures were elucidated based on their spectroscopic data, and their NMR data were compared with those in the literature. Compounds 3-6 potently inhibited the Wnt signal with IC50 values of 127 nM, 300 nM, 252 nM, and 121 nM, respectively. Compound 4 exhibited selective cytotoxicity against AGS and HCT116. Western blot analysis showed that 4 did not affect the level or localization of beta-catenin, but downregulated the level of c-myc. Our results suggested that 4 may have inhibited the Wnt signal by affecting the components downstream of beta-catenin. (C) 2015 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

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ヘッジホッグシグナル阻害活性を有するヘテロ環含有フラボノイドの合成と活性評価

荒井緑, 内海尊雄, 米山達朗, 野尻奈那, 石橋正己

日本薬学会年会要旨集 ((公社)日本薬学会) 135年会 ( 2 ) 188 - 188 2015.03

ISSN 0918-9823

Inubosins A, B, and C Are Acridine Alkaloids Isolated from a Culture of Streptomyces sp IFM 11440 with Ngn2 Promoter Activity

Midori A. Arai, Kazune Koryudzu, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 78 ( 2 ) 311 - 314 2015.02

Accepted, ISSN 0163-3864

Three new acridine alkaloids, inubosins A (1), B (2), and C (3), were isolated from an extract of a culture of Streptomyces sp. IFM 11440 using bioassay-guided fractionation. Neurogenin2 (Ngn2) is an activator-type basic helix-loop-helix transcription factor that promotes neural stem cell differentiation. Using cell-based Ngn2 promoter activity-guided screening, Streptomyces sp. IFM 11440 was found to induce Ngn2 promoter activity. The structures of 1-3 were established using spectroscopic methods, including 1D- and 2D-NMR measurements. Inubosin B (2) showed potent Ngn2 promoter activity. Moreover, inubosin B (2) increased mRNA expression of genes related to neural stem cell differentiation.

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ISOLATION OF ALKAMIDES WITH DEATH RECEPTOR-ENHANCING ACTIVITIES FROM PIPER CHABA

Hogue Tahmina, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

HETEROCYCLES (PERGAMON-ELSEVIER SCIENCE LTD) 90 ( 2 ) 1317 - 1322 2015.01

Accepted, ISSN 0385-5414

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Prenylated Flavonoids and Resveratrol Derivatives Isolated from Artocarpus communis with the Ability to Overcome TRAIL Resistance

Toume, Kazufumi, Habu, Tadashi, Arai, Midori A., Koyano, Takashi, Kowithayakorn, Thaworn, Ishibashi, Masami

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 78 ( 1 ) 103 - 110 2015.01

Accepted, ISSN 0163-3864

In a screening program on natural products that can abrogate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance, four new prenylated flavonoid and resveratrol derivatives (1-4) were isolated from Artocarpus communis, together with eight known prenylflavonoids (5-12). The structures of 1-4 were elucidated spectroscopically. Pannokin E (1) (2 mu M) and artonin E (5) (3 mu M) potently exhibited the ability to overcome TRAIL resistance. Artonin E (5) induced caspase-dependent apoptosis in combination with TRAIL, increased caspase 3/7 activity, and enhanced the protein levels of p53 and DR5. Moreover, this substance decreased cell viability in combination with TRAIL and enhanced the protein levels of DR5, and these effects were mediated by increases in the production of ROS (reactive oxygen species). Thus, artonin E (5) was found to induce extrinsic apoptotic cell death by the ROS- and p53-mediated up-regulation of DR5 expression in AGS cells.

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Natural compounds with Wnt signal modulating activity

Rolly G. Fuentes, Midori A. Arai, Masami Ishibashi

NATURAL PRODUCT REPORTS (ROYAL SOC CHEMISTRY) 32 ( 12 ) 1622 - 1628 2015

Accepted, ISSN 0265-0568

The Wnt signalling pathway is essential in many biological processes. The Wnt signal is associated with several diseases, particularly cancer and neurodegenerative diseases. Recently, high-throughput screening systems have been developed to rapidly identify compounds, including natural compounds, that target the Wnt signal. Some studies on natural modulators of the Wnt signal have also suggested their possible target. This review highlights some important natural compounds reported to regulate Wnt activity and describes their possible mechanism of action.

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Naturally occurring FANCF-Hes1 complex inhibitors from Wrightia religiosa

Midori A. Arai, Kenji Uemura, Nozomi Hamahiga, Naoki Ishikawa, Takashi Koyano, Thaworn Kowithayakorn, Tagrid Kaddar, Madeleine Carreau, Masami Ishibashi

MEDCHEMCOMM (ROYAL SOC CHEMISTRY) 6 ( 3 ) 455 - 460 2015

Accepted, ISSN 2040-2503

The isolation and evaluation of inhibitors of Fanconi F protein (FANCF) - haity and enhancer of split 1 (Hes1) complex are described. A high-throughput screening assay for small-molecule inhibitors of the FANCF-Hes1 complex was realized. Successful complex formation between fluorophore (Cy3)-labeled human FANCF and immobilized rat or human HES1 on a microplate was established. Screening of our plant extract library using this system resulted in the isolation of eight natural products, including two new flavonoid glycosides (3 and 4), from Wrightia religiosa. Of these compounds, 3, 5, and 7 showed potent inhibition of the FANCF-Hes1 complex formation. Compound 7 disrupted the FANCF-Hes1 complex more efficiently than the Hes1 dimer.

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Prenylflavonoids isolated from Artocarpus champeden with TRAIL-resistance overcoming activity (vol 96, pg 299, 2013)

Tomohiro Minakawa, Kazufumi Toume, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

PHYTOCHEMISTRY (PERGAMON-ELSEVIER SCIENCE LTD) 106 207 - 207 2014.10

Accepted, ISSN 0031-9422

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Ricinine: A pyridone alkaloid from Ricinus communis that activates the Wnt signaling pathway through casein kinase 1 alpha

Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Takamasa Mizoguchi, Motoyuki Itoh, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY (PERGAMON-ELSEVIER SCIENCE LTD) 22 ( 17 ) 4597 - 4601 2014.09

Accepted, ISSN 0968-0896

Wnt signaling plays important roles in proliferation, differentiation, development of cells, and various diseases. Activity-guided fractionation of the MeOH extract of the Ricinus communis stem led to the isolation of four compounds (1-4). The TCF/beta-catenin transcription activities of 1 and 3 were 2.2 and 2.5 fold higher at 20 and 30 mu M, respectively. Cells treated with ricinine (1) had higher beta-catenin and lower of p-beta-catenin (ser 33, 37, 45, Thr 41) protein levels, whereas glycogen synthase kinase 3 beta (GSK3 beta) and casein kinase 1 alpha (CK1 alpha) protein levels remained unchanged. Cells treated with pyrvinium, an activator of CK1 alpha, had lower beta-catenin levels. However, the combined treatment of pyrvinium and 1 led to higher beta-catenin levels than those in cells treated with pyrvinium alone, which suggested that 1 inhibited CK1 alpha activity. Furthermore, 1 increased beta-catenin protein levels in zebrafish embryos. These results indicated that 1 activated the Wnt signaling pathway by inhibiting CK1 alpha. (C) 2014 Elsevier Ltd. All rights reserved.

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Themeda arguens等からのヘッジホッグ伝達経路阻害剤の探索

米山達朗, 荒井緑, 小谷野喬, Kowithayakorn Thaworn, Sadhu Samir K., Ahmed Firoj, 石橋正己

日本生薬学会年会講演要旨集 ((一社)日本生薬学会) 61回 113 - 113 2014.08

ISSN 0919-1992

Chromomycins A(2) and A(3) from Marine Actinomycetes with TRAIL Resistance-Overcoming and Wnt Signal Inhibitory Activities

Toume, Kazufumi, Tsukahara, Kentaro, Ito, Hanako, Arai, Midori A., Ishibashi, Masami

MARINE DRUGS (MDPI AG) 12 ( 6 ) 3466 - 3476 2014.06

Accepted, ISSN 1660-3397

A biological screening study of an actinomycetes strain assembly was conducted using a cell-based cytotoxicity assay. The CKK1019 strain was isolated from a sea sand sample. Cytotoxicity-guided fractionation of the CKK1019 strain culture broth, which exhibited cytotoxicity, led to the isolation of chromomycins A(2) (1) and A(3) (2). 1 and 2 showed potent cytotoxicity against the human gastric adenocarcinoma (AGS) cell line (IC50 1; 1.7 and 2; 22.1 nM), as well as strong inhibitory effects against TCF/beta-catenin transcription (IC50 1; 1.8 and 2; 15.9 nM). 2 showed the ability to overcome tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance. To the best of our knowledge, the effects of chromomycins A(2) (1) and A(3) (2) on TRAIL resistance-overcoming activity, and on the Wnt signaling pathway, have not been reported previously. Thus, 1 and 2 warrant potential drug lead studies in relation to TRAIL-resistant and Wnt signal-related diseases and offer potentially useful chemical probes for investigating TRAIL resistance and the Wnt signaling pathway.

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Calotropin: A Cardenolide from Calotropis gigantea that Inhibits Wnt Signaling by Increasing Casein Kinase 1 alpha in Colon Cancer Cells

Hyun Young Park, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

CHEMBIOCHEM (WILEY-V C H VERLAG GMBH) 15 ( 6 ) 872 - 878 2014.04

Accepted, ISSN 1439-4227

Wnt signaling plays key roles in embryonic development and various human diseases. Activity-guided testing to isolate Wnt signaling inhibitors from the methanol extract of Calotropis gigantea (Asclepiadaceae) exudutes identified six Wnt inhibitory cardenolides (1-6), of which 1, 3, 5, and 6 exhibited potent TCF/-catenin inhibitory activities (IC50 0.7-3.6 nM). Calotropin (1) inhibited Wnt signaling by decreasing both nuclear and cytosolic -catenin in a dose-dependent manner, and promoted degradation of -catenin by increasing the phosphorylation of -catenin at Ser45 through casein kinase 1 (CK1). Moreover, 1 significantly increased CK1 protein and mRNA levels. The results suggest that 1 inhibits the Wnt signaling pathway by increasing CK1 protein levels. To the best of our knowledge, calotropin is the first small molecule to increase CK1 levels.

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Themeda arguens等からのヘッジホッグ伝達経路阻害剤の探索

米山達朗, 荒井緑, 小谷野喬, Kowithayakorn Thaworn, Sadhu Samir K., Ahmed Firoj, 石橋正己

日本薬学会年会要旨集 ((公社)日本薬学会) 134年会 ( 2 ) 71 - 71 2014.03

ISSN 0918-9823

Eudesmane-Type Sesquiterpenoid and Guaianolides from Kandelia candel in a Screening Program for Compounds to Overcome TRAIL Resistance (vol 75, pg 1431, 2012)

Tomohiro Minakawa, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 77 ( 2 ) 437 - 437 2014.02

Accepted, ISSN 0163-3864

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