Discovery of incednine as a potent modulator of the anti-apoptotic function of Bcl-xL from microbial origin

Yushi Futamura, Ryuichi Sawa, Yoji Umezawa, Masayuki Igarashi, Hikaru Nakamura, Kimiko Hasegawa, Mikio Yamasaki, Etsu Tashiro, Yoshikazu Takahashi, Yuzuru Akamatsu, Masaya Imoto

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45 Citations (Scopus)

Abstract

Anti-apoptotic oncoproteins Bcl-2 and Bcl-xL are overexpressed in many cancers and play a crucial role in cancer initiation, progression, and resistance to chemotherapy. Therefore, the discovery of a functional inhibitor for these proteins and improved understanding of the molecular mechanisms of these proteins will be an aid to novel anti-tumor therapies. Here, using chemical-genetic cell-based screening, we have discovered a chemically and biologically unique substance, incednine, as a novel functional modulator of Bcl-2/Bcl-xL from the fermentation broth of Streptomyces sp. ML693-90F3. This compound was isolated as a HCl salt by solvent extraction and using centrifugal liquid-liquid partition chromatography. Its structure was elucidated by spectroscopic analysis, X-ray crystallographic analysis, and computational studies. Incednine has a molecular formula, C42H63N3O8, and consists of a novel skeletal structure, enol-ether amide in a 24-membered macrolactam core, with two aminosugars. Bcl-xL-overexpressing Ms-1 cells displayed resistance to several anti-tumor agents; however, anti-tumor agent-induced cell death was observed only when cells were treated with incednine. Overexpression of Bcl-xL inhibited cell death in Bax-overexpressing HEK293T cells by forming a complex with Bax, whereas Bcl-xL failed to inhibit cell death in the presence of incednine without affecting the heterodimerization of Bcl-xL and Bax. These findings suggest that incednine serves as a potent modulator of the anti-apoptotic Bcl-2/Bcl-xL distinct from the other known Bcl-2 inhibitors and could provide a chemical probe to study the underlying mechanisms of Bcl-2/Bcl-xL.

Original languageEnglish
Pages (from-to)1822-1823
Number of pages2
JournalJournal of the American Chemical Society
Volume130
Issue number6
DOIs
Publication statusPublished - 2008 Feb 13

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Futamura, Y., Sawa, R., Umezawa, Y., Igarashi, M., Nakamura, H., Hasegawa, K., Yamasaki, M., Tashiro, E., Takahashi, Y., Akamatsu, Y., & Imoto, M. (2008). Discovery of incednine as a potent modulator of the anti-apoptotic function of Bcl-xL from microbial origin. Journal of the American Chemical Society, 130(6), 1822-1823. https://doi.org/10.1021/ja710124p