Back to Search
Start Over
Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2008 Oct; Vol. 7 (10), pp. 3298-305. - Publication Year :
- 2008
-
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.
- Subjects :
- Animals
Annexin A5 metabolism
Antineoplastic Agents pharmacology
Cell Proliferation drug effects
Humans
Male
Mice
Mice, Inbred BALB C
Propidium metabolism
Proto-Oncogene Proteins c-mdm2 genetics
Transcription, Genetic drug effects
Tumor Suppressor Protein p53 genetics
Up-Regulation drug effects
Xanthones chemistry
Xenograft Model Antitumor Assays
Apoptosis drug effects
Down-Regulation drug effects
Neoplasms metabolism
Neoplasms pathology
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 metabolism
Xanthones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-7163
- Volume :
- 7
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 18852133
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-08-0212