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

• Published in: Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (9), p.2994-2997
• Main Authors: Nakashima, Souichi, Matsuda, Hisashi, Kurume, Ai, Oda, Yoshimi, Nakamura, Seikou, Yamashita, Masayuki, Yoshikawa, Masayuki
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Biological and medical sciences; Biotin-linked cucurbitacin E; Cell Line, Tumor; Cofilin; Cofilin 1 - antagonists & inhibitors; Cofilin 1 - metabolism; Cucurbitacin E; Cucurbitane-type triterpene; Cytotoxic effect; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; STAT3 Transcription Factor - metabolism; Target protein; Triterpenes - chemistry; Triterpenes - toxicity; U937 Cells
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.062

We 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. 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.