title: Monocillin II inhibits human breast cancer growth partially by inhibiting MAPK pathways and CDK2 Thr160 phosphorylation.
abstract: 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.
authors.affiliation: Key Laboratory of Molecular Medicine, the Ministry of Education, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Wei
authors.forename: Liangxiong
authors.initials: L
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Huijie
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Wei
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013912:Threonine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007783:Lactones; C548475:monocillin II; D013912:Threonine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020928:Mitogen-Activated Protein Kinases