2. Academic Validation
  3. Hedgehog inhibitors from Withania somnifera

Hedgehog inhibitors from Withania somnifera

  • Bioorg Med Chem Lett. 2015 Sep 1;25(17):3541-4. doi: 10.1016/j.bmcl.2015.06.081.
Tatsuro Yoneyama 1,  Midori A Arai 2,  Samir K Sadhu 3,  Firoj Ahmed 4,  Masami Ishibashi 5
Affiliations

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.

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