New hedgehog/GLI-signaling inhibitors from Adenium obesum

Midori A. Arai; Chikashi Tateno; Takashi Koyano; Thaworn Kowithayakorn; Seiichiro Kawabe; Masami Ishibashi

doi:10.1039/c0ob00677g

New hedgehog/GLI-signaling inhibitors from Adenium obesum

Midori A. Arai, Chikashi Tateno, Takashi Koyano, Thaworn Kowithayakorn, Seiichiro Kawabe, Masami Ishibashi

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36 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1133-1139
Number of pages	7
Journal	Organic and Biomolecular Chemistry
Volume	9
Issue number	4
DOIs	https://doi.org/10.1039/c0ob00677g
Publication status	Published - 2011 Feb 21
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

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Arai, M. A., Tateno, C., Koyano, T., Kowithayakorn, T., Kawabe, S., & Ishibashi, M. (2011). New hedgehog/GLI-signaling inhibitors from Adenium obesum. Organic and Biomolecular Chemistry, 9(4), 1133-1139. https://doi.org/10.1039/c0ob00677g

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abstract = "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.",

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