Hedgehog inhibitors from Withania somnifera

Tatsuro Yoneyama; Midori A. Arai; Samir K. Sadhu; Firoj Ahmed; Masami Ishibashi

doi:10.1016/j.bmcl.2015.06.081

Hedgehog inhibitors from Withania somnifera

Tatsuro Yoneyama, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC₅₀ values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA.

Original language	English
Pages (from-to)	3541-3544
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2015.06.081
Publication status	Published - 2015 Aug 3
Externally published	Yes

Keywords

Hedgehog signaling pathway
Inhibitor
Natural product
Withania somnifera

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2015.06.081

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@article{576858f56ab04120b358e93768bc65cf,

title = "Hedgehog inhibitors from Withania somnifera",

abstract = "The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA.",

keywords = "Hedgehog signaling pathway, Inhibitor, Natural product, Withania somnifera",

author = "Tatsuro Yoneyama and Arai, {Midori A.} and Sadhu, {Samir K.} and Firoj Ahmed and Masami Ishibashi",

note = "Funding Information: We are very grateful to Drs. Fritz Aberger and Gerhard Regl (University of Salzburg) for providing us with tetracycline-regulated HaCaT cells, Dr. Rune Toftg{\aa}rd (Karolinska Institute) for the 12GLI-RE-TKO luciferase plasmid, Dr. Bert Vogelstein (Howard Hughes Medical Institute) and Dr. Hiroshi Sasaki (RIKEN) for the human GLI1 plasmid. This study was supported by KAKENHI Grant Numbers 26305001, 26293022, and 25670045 from JSPS, and 23102008 from MEXT (a Grant-in-Aid for Scientific Research on Innovative Areras in {\textquoteleft}Chemical Biology of Natural Products{\textquoteright}). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

year = "2015",

month = aug,

day = "3",

doi = "10.1016/j.bmcl.2015.06.081",

language = "English",

volume = "25",

pages = "3541--3544",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "17",

}

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T1 - Hedgehog inhibitors from Withania somnifera

AU - Yoneyama, Tatsuro

AU - Arai, Midori A.

AU - Sadhu, Samir K.

AU - Ahmed, Firoj

AU - Ishibashi, Masami

N1 - Funding Information: We are very grateful to Drs. Fritz Aberger and Gerhard Regl (University of Salzburg) for providing us with tetracycline-regulated HaCaT cells, Dr. Rune Toftgård (Karolinska Institute) for the 12GLI-RE-TKO luciferase plasmid, Dr. Bert Vogelstein (Howard Hughes Medical Institute) and Dr. Hiroshi Sasaki (RIKEN) for the human GLI1 plasmid. This study was supported by KAKENHI Grant Numbers 26305001, 26293022, and 25670045 from JSPS, and 23102008 from MEXT (a Grant-in-Aid for Scientific Research on Innovative Areras in ‘Chemical Biology of Natural Products’). Publisher Copyright: © 2015 Elsevier Ltd.

PY - 2015/8/3

Y1 - 2015/8/3

N2 - The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA.

AB - The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA.

KW - Hedgehog signaling pathway

KW - Inhibitor

KW - Natural product

KW - Withania somnifera

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ER -

Hedgehog inhibitors from Withania somnifera

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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