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: Han-Zhang Xu, Ying Huang, Ying-Li Wu, Yong Zhao, Wei-Lie Xiao, Qi-Shan Lin, Han-Dong Sun, Wei Dai, Guo-Qiang Chen
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 9 Issue 14 Pg. 2897-907 (Jul 15 2010) ISSN: 1551-4005 [Electronic] United States
• PMID: 20603598 (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)