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Nakano-ku, Japan

Arai M.A.,Chiba University | Tateno C.,Chiba University | Koyano T.,Temko Corporation | Kowithayakorn T.,Khon Kaen University | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2011

The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1-17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC50 of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited. © 2011 The Royal Society of Chemistry. Source


Rifai Y.,Chiba University | Arai M.A.,Chiba University | Koyano T.,Temko Corporation | Kowithayakorn T.,Khon Kaen University | Ishibashi M.,Chiba University
Journal of Natural Medicines | Year: 2011

Complete 1H and 13C NMR assignments of acoschimperoside P, 2′-acetate (1) and a new cardiac glycoside (2), isolated from the leaves of Vallaris glabra, are described. Compound 1 was active in the assay for Hedgehog signaling inhibition. In further experiments, this compound showed a strong cytotoxicity against human pancreatic (PANC1) and human prostate (DU145) cancer cells. The expression of GLI-related proteins (PTCH and BCL-2) in a dose-dependent manner was also inhibited by 1. © 2011 The Japanese Society of Pharmacognosy and Springer. Source


Kikuchi H.,Chiba University | Ohtsuki T.,Chiba University | Koyano T.,Temko Corporation | Kowithayakorn T.,Khon Kaen University | And 2 more authors.
Journal of Natural Products | Year: 2010

A screening study using a luciferase assay to identify natural products that enhance death receptor 5 (DR5) expression was carried out, and bioassay-guided fractionation of two organisms, the pericarp of Garcinia mangostana (mangosteen) and actinomycete CKK609 strain, led to the isolation of eight xanthone derivatives (1- 8) and teleocidin A-2 (9), Among them, compounds 1, 2, and 5, isolated from G. mangostana, and 9, from the actinomycete, showed potent DR5 promoter activity. Furthermore, we revealed that combined treatment with gartanin (5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) showed a potentiation effect in sensitizing TRAIL-resistant human gastric adenocarcinoma (AGS) cells. Thus, the present results suggested that 5 has the ability to overcome TRAIL resistance via the up-regulation of DR5 and may be an effective sensitizer of TRAIL-resistant cells. © 2010 American Chemical Society and American Society of Pharmacognosy. Source


Rifai Y.,Chiba University | Arai M.A.,Chiba University | Koyano T.,Temko Corporation | Kowithayakorn T.,Khon Kaen University | Ishibashi M.,Chiba University
Journal of Natural Products | Year: 2010

Overexpression of glioma-associated oncogene 1 (GLI1), which has been characterized as a terminal effector and a target gene of the Hedgehog (Hh) signaling pathway, is associated with the development of cancer. A cellular screen was applied utilizing of a GLI-dependent luciferase reporter in human keratinocyte cells (HaCaT) and identified two terpenoids (1 and 2) and a flavonoid glycoside (5) from Acacia pennata as Hh/GLI inhibitors. Compounds 1, 2, and 5 exhibited selective cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells with no toxic effect on normal cells. This result was consistent with a dose-dependent reduction of the protein levels of antiapoptotic BCL-2 and the tumor suppressor patched 1 protein (PTCH). Additionally, treatment of 1 downregulated mRNA expression of Ptch in PANC1, suggesting that the compound has an inhibitory effect on the transcription of Hh/GLI. © 2010 The American Chemical Society and American Society of Pharmacognosy. Source


Arai M.A.,Chiba University | Koryudzu K.,Chiba University | Koyano T.,Temko Corporation | Kowithayakorn T.,Khon Kaen University | Ishibashi M.,Chiba University
Molecular BioSystems | Year: 2013

Neurogenin2 (Ngn2), an activator-type bHLH transcriptional factor, promotes differentiation of neural stem cells into neurons by transcription of pro-neural genes. To find neural stem cell accelerators from the extract library of natural resources, we used a two-step screening including a Ngn2 promoter reporter gene screening and differentiation assay screening of neural stem cells. A reporter gene assay that can detect Ngn2 promoter activity by luciferase expression was constructed using C3H10T1/2 cells. Using this primary cell-based screening, Butea superba was found to include Ngn2 promoter activators from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 18 natural products, including pterocarpans and isoflavonoids. Dehydromaackiain (1), formononetin (6), (-)-variabilin (13), (-)-medicarpin (14), rothindin (17) and ononin (18) showed 1.8-2.8 times higher Ngn2 promoter activity at 5 μM compared with control. Of active natural compounds, 3′-methoxydaidzein (3) showed promotion of neurite outgrowth of C17.2 in a secondary screen. 3′-Methoxydaidzein (3) increased mRNA expression of pro-neural transcriptional factors (Ngn2, Ngn1, NeuroD2), a mature neuron-specific enzyme GAD1 and a pro-neural neurotrophic growth factor neurotrophin 3 (NT3) in C17.2 neural stem cells. © 2013 The Royal Society of Chemistry. Source

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