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

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3541-4. doi: 10.1016/j.bmcl.2015.06.081. Epub 2015 Jun 30.

Authors

Tatsuro Yoneyama¹, Midori A Arai², Samir K Sadhu³, Firoj Ahmed⁴, Masami Ishibashi⁵

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
² Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: midori_arai@chiba-u.jp.
³ Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
⁴ Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh.
⁵ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: mish@chiba-u.jp.

PMID: 26169123
DOI: 10.1016/j.bmcl.2015.06.081

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Phytogenic / chemistry*
Antineoplastic Agents, Phytogenic / isolation & purification
Antineoplastic Agents, Phytogenic / pharmacology*
Cell Line, Tumor
Female
Hedgehog Proteins / antagonists & inhibitors*
Hedgehog Proteins / metabolism
Humans
Male
Neoplasms / drug therapy
Neoplasms / metabolism
Signal Transduction / drug effects
Withania / chemistry*
Withanolides / chemistry*
Withanolides / isolation & purification
Withanolides / pharmacology*

Substances

Antineoplastic Agents, Phytogenic
Hedgehog Proteins
Withanolides
withaferin A