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Monocillin II Inhibits Human Breast Cancer Growth Partially by Inhibiting MAPK Pathways and CDK2 Thr160 Phosphorylation
Author(s) -
Wei Huanhuan,
Xu Liangxiong,
Yu Min,
Zhang Ling,
Wang Huijie,
Wei Xiaoyi,
Ruan Yuanyuan
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100558
Subject(s) - cyclin dependent kinase 2 , mapk/erk pathway , protein kinase a , cancer research , kinase , phosphorylation , chemistry , cyclin dependent kinase 1 , p38 mitogen activated protein kinases , cell growth , cell cycle , cyclin dependent kinase , cell cycle checkpoint , microbiology and biotechnology , biochemistry , biology , apoptosis
Twenty‐two β‐resorcylic acid lactones (RALs) were evaluated for cytotoxicity against human breast cancer cells to find their structure–activity relationship (SAR). Monocillin II, a trans‐ enone RAL without epoxy and conjugated dienone, was found to have higher activity in inhibiting tumor cell growth in both in vitro experiment and in vivo nude xenografted mice model than its analogue radicicol, an anticancer lead compound. We demonstrated for the first time that monocillin II could arrest breast cancer cell cycle in G1 phase, which might partially be the result of its inhibition effect on the phosphorylation of the Thr160 residue of cyclin dependent kinase 2 (CDK2), a key enzyme in cell‐cycle regulation. Moreover, monocillin II exhibited inhibition of heat shock protein 90 (Hsp90) and depleted its target proteins, Raf‐1 and A‐Raf, which are involved in Ras/Raf/MEK/ERK mitogen‐activated protein kinase (MAPK) pathway. Remarkably, we found that monocillin II could inhibit activation of MAPKs including ERK, JNK and p38, which might be involved in the inactivation of CDK2. These results suggest that monocillin II has potential therapeutic benefits in breast cancer prevention and intervention.