Cucurbitacin E as a new inhibitor of cofilin phosphorylation in human leukemia U937 cells.

Abstract

Cucurbitane-type triterpenes, cucurbitacins B and E, were reported to exhibit cytotoxic effects in several cell lines mediated by JAK/STAT3 signaling. However, neither compound inhibited phosphorylation of STAT3 in human leukemia (U937) cells at low concentrations. We therefore synthesized a biotin-linked cucurbitacin E to isolate target proteins based on affinity for the molecule. As a result, cofilin, which regulates the depolymerization of actin, was isolated and suggested to be a target. Cucurbitacins E and I inhibited the phosphorylation of cofilin in a concentration-dependent manner, and their effective concentrations having the same range as the concentrations at which they had cytotoxic effects in U937 cells. In addition, the fibrous-/globular-actin ratio was decreased after treatment with cucurbitacin E in HT1080 cells. These findings suggested that the inhibition of cofilin's phosphorylation increased the severing activity of cofilin, and then the depolymerization of actin was enhanced after treatment with cucurbitacin E at lower concentrations.

• Authors: Souichi Nakashima, Hisashi Matsuda, Ai Kurume, Yoshimi Oda, Seikou Nakamura, Masayuki Yamashita, Masayuki Yoshikawa
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 9 Pg. 2994-7 (May 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20347305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Actins
• Antineoplastic Agents
• Cofilin 1
• STAT3 Transcription Factor
• STAT3 protein, human
• Triterpenes
• cucurbitacin B
• cucurbitacin I
• cucurbitacin E

Topics

• Actins (metabolism)
• Antineoplastic Agents (chemistry, toxicity)
• Cell Line, Tumor
• Cofilin 1 (antagonists & inhibitors, metabolism)
• Humans
• Phosphorylation
• STAT3 Transcription Factor (metabolism)
• Triterpenes (chemistry, toxicity)
• U937 Cells