Journal
BRITISH JOURNAL OF CANCER
Volume 102, Issue 1, Pages 104-114Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605408
Keywords
phosphoinositide 3-kinase; inositol polyphosphates; protein kinase B-Akt; 3-phosphoinositide-dependent protein kinase 1; apoptosis
Categories
Funding
- European Commission [037344]
- American Institute for Cancer Research
- Pancreatic Cancer Research Fund
- Wellcome Trust
- Italian Association for Cancer Research
- Fondazione Carichieti
- British Heart Foundation [PG/04/033/16906]
- Italian Foundation for Cancer Research (FIRC)
Ask authors/readers for more resources
BACKGROUND: Owing to its role in cancer, the phosphoinositide 3-kinase (PI3K)/Akt pathway is an attractive target for therapeutic intervention. We previously reported that the inhibition of Akt by inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) results in anti-tumour properties. To further develop this compound we modified its structure to obtain more potent inhibitors of the PI3K/Akt pathway. METHODS: Cell proliferation/survival was determined by cell counting, sulphorhodamine or acridine orange/ethidium bromide assay; Akt activation was determined by western blot analysis. In vivo effect of compounds was tested on PC3 xenografts, whereas in vitro activity on kinases was determined by SelectScreen Kinase Profiling Service. RESULTS: The derivative 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP(5)) is active towards cancer types resistant to InsP(5) in vitro and in vivo. 2-O-Bn-InsP(5) possesses higher pro-apoptotic activity than InsP(5) in sensitive cells and enhances the effect of anti-cancer compounds. 2-O-Bn-InsP(5) specifically inhibits 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro (IC50 in the low nanomolar range) and the PDK1-dependent phosphorylation of Akt in cell lines and excised tumours. It is interesting to note that 2-O-Bn-InsP(5) also inhibits the mammalian target of rapamycin (mTOR) in vitro. CONCLUSIONS: InsP(5) and 2-O-Bn-InsP(5) may represent lead compounds to develop novel inhibitors of the PI3K/Akt pathway (including potential dual PDK1/mTOR inhibitors) and novel potential anti-cancer drugs. British Journal of Cancer (2010) 102, 104-114. doi:10.1038/sj.bjc.6605408 www.bjcancer.com (C) 2010 Cancer Research UK
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available