Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells.

Abstract

Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-iumbromide assay, (3)H-thymidine incorporation analysis, and an in vivo mouse xenograft model. GA induced massive cell apoptosis as judged by Annexin V and propidium iodide dual-staining experiments. Furthermore, we found that GA partially induced cancer cell growth inhibition in a p53-dependent manner because cell survival could be restored after endogenous p53 was attenuated by p53 transcriptional repressor pifithrin-alpha or p53 small interfering RNA. Interestingly, GA had no influence on p53 mRNA synthesis but dramatically enhanced its protein expression. This unique observation could be accounted for by the down-regulation of mdm2 at both mRNA and protein levels. It is concluded that GA enhances p53 protein level through inhibition of mdm2 expression and thereby hampers p53 harboring tumor growth.

• Authors: Hongyan Gu, Xiaotang Wang, Shuyun Rao, Jia Wang, Jie Zhao, Fang Li Ren, Rong Mu, Yong Yang, Qi Qi, Wei Liu, Na Lu, Hua Ling, Qidong You, Qinglong Guo
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 10 Pg. 3298-305 (Oct 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18852133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• Antineoplastic Agents
• Tumor Suppressor Protein p53
• Xanthones
• Propidium
• gambogic acid
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Annexin A5 (metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Neoplasms (metabolism, pathology)
• Propidium (metabolism)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Up-Regulation (drug effects)
• Xanthones (chemistry, pharmacology)
• Xenograft Model Antitumor Assays