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

Research output: Contribution to journalArticle

42 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

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Cell death
Modulators
Tumors
Cell Death
Proteins
Neoplasms
Spectroscopic analysis
Chemotherapy
Liquids
Solvent extraction
Chromatography
Amides
Fermentation
Ethers
Screening
Salts
Oncogene Proteins
Streptomyces
X rays
Liquid Chromatography

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Discovery of incednine as a potent modulator of the anti-apoptotic function of Bcl-xL from microbial origin. / Futamura, Yushi; Sawa, Ryuichi; Umezawa, Yoji; Igarashi, Masayuki; Nakamura, Hikaru; Hasegawa, Kimiko; Yamasaki, Mikio; Tashiro, Etsu; Takahashi, Yoshikazu; Akamatsu, Yuzuru; Imoto, Masaya.

In: Journal of the American Chemical Society, Vol. 130, No. 6, 13.02.2008, p. 1822-1823.

Research output: Contribution to journalArticle

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, vol. 130, no. 6, pp. 1822-1823. https://doi.org/10.1021/ja710124p
Futamura, Yushi ; Sawa, Ryuichi ; Umezawa, Yoji ; Igarashi, Masayuki ; Nakamura, Hikaru ; Hasegawa, Kimiko ; Yamasaki, Mikio ; Tashiro, Etsu ; Takahashi, Yoshikazu ; Akamatsu, Yuzuru ; Imoto, Masaya. / Discovery of incednine as a potent modulator of the anti-apoptotic function of Bcl-xL from microbial origin. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 6. pp. 1822-1823.
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