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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.
AuthorsHan-Zhang Xu, Ying Huang, Ying-Li Wu, Yong Zhao, Wei-Lie Xiao, Qi-Shan Lin, Han-Dong Sun, Wei Dai, Guo-Qiang Chen
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 9 Issue 14 Pg. 2897-907 (Jul 15 2010) ISSN: 1551-4005 [Electronic] United States
PMID20603598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Diterpenes, Kaurane
  • pharicin A
  • BUB1 protein, human
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase
Topics
  • Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
  • CDC2 Protein Kinase (metabolism)
  • Chromatids (drug effects)
  • Diterpenes, Kaurane (chemistry, isolation & purification, pharmacology)
  • Humans
  • Isodon (chemistry)
  • Jurkat Cells
  • Medicine, Chinese Traditional
  • Mitosis (drug effects)
  • Protein-Serine-Threonine Kinases (analysis, antagonists & inhibitors, metabolism)

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