title: Pharicin A, a novel natural ent-kaurene diterpenoid, induces mitotic arrest and mitotic catastrophe of cancer cells by interfering with BubR1 function.
abstract: In this study, we report the functional characterization of a new ent-kaurene diterpenoid termed pharicin A, which was originally isolated from Isodon, a perennial shrub frequently used in Chinese folk medicine for tumor treatment. Pharicin A induces mitotic arrest in leukemia and solid tumor-derived cells identified by their morphology, DNA content and mitotic marker analyses. Pharicin A-induced mitotic arrest is associated with unaligned chromosomes, aberrant BubR1 localization and deregulated spindle checkpoint activation. Pharicin A directly binds to BubR1 in vitro, which is correlated with premature sister chromatid separation in vivo. Pharicin A also induces mitotic arrest in paclitaxel-resistant Jurkat and U2OS cells. Combined, our study strongly suggests that pharicin A represents a novel class of small molecule compounds capable of perturbing mitotic progression and initiating mitotic catastrophe, which merits further preclinical and clinical investigations for cancer drug development.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Han-Zhang
authors.initials: HZ
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei-Lie
authors.initials: WL
authors.lastname: Xiao
authors.forename: Qi-Shan
authors.initials: QS
authors.lastname: Lin
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002842:Chromatids / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D037602:Isodon / Q000737:chemistry; D019169:Jurkat Cells; D008516:Medicine, Chinese Traditional; D008938:Mitosis / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; C555529:pharicin A; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase