Abstract
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 (InsP5) 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-InsP5) is active towards cancer types resistant to InsP5 in vitro and in vivo. 2-O-Bn-InsP5 possesses higher pro-apoptotic activity than InsP 5 in sensitive cells and enhances the effect of anti-cancer compounds. 2-O-Bn-InsP5 specifically inhibits 3-phosphoinositide- dependent protein kinase 1 (PDK1) in vitro (IC 50 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-InsP5 also inhibits the mammalian target of rapamycin (mTOR) in vitro.Conclusions: InsP5 and 2-O-Bn-InsP5 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.
| Original language | English |
|---|---|
| Pages (from-to) | 104-114 |
| Number of pages | 11 |
| Journal | British Journal of Cancer |
| Volume | 102 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2010 |
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Keywords
- 3-phosphoinositide-dependent protein kinase 1
- Apoptosis
- Inositol polyphosphates
- Phosphoinositide 3-kinase
- Protein kinase B-Akt
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. / Falasca, M.; Chiozzotto, D.; Godage, H. Y.; Mazzoletti, M.; Riley, A. M.; Previdi, S.; Potter, B. V L; Broggini, M.; Maffucci, T.
In: British Journal of Cancer, Vol. 102, No. 1, 01.2010, p. 104-114.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate
AU - Falasca, M.
AU - Chiozzotto, D.
AU - Godage, H. Y.
AU - Mazzoletti, M.
AU - Riley, A. M.
AU - Previdi, S.
AU - Potter, B. V L
AU - Broggini, M.
AU - Maffucci, T.
PY - 2010/1
Y1 - 2010/1
N2 - 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 (InsP5) 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-InsP5) is active towards cancer types resistant to InsP5 in vitro and in vivo. 2-O-Bn-InsP5 possesses higher pro-apoptotic activity than InsP 5 in sensitive cells and enhances the effect of anti-cancer compounds. 2-O-Bn-InsP5 specifically inhibits 3-phosphoinositide- dependent protein kinase 1 (PDK1) in vitro (IC 50 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-InsP5 also inhibits the mammalian target of rapamycin (mTOR) in vitro.Conclusions: InsP5 and 2-O-Bn-InsP5 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.
AB - 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 (InsP5) 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-InsP5) is active towards cancer types resistant to InsP5 in vitro and in vivo. 2-O-Bn-InsP5 possesses higher pro-apoptotic activity than InsP 5 in sensitive cells and enhances the effect of anti-cancer compounds. 2-O-Bn-InsP5 specifically inhibits 3-phosphoinositide- dependent protein kinase 1 (PDK1) in vitro (IC 50 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-InsP5 also inhibits the mammalian target of rapamycin (mTOR) in vitro.Conclusions: InsP5 and 2-O-Bn-InsP5 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.
KW - 3-phosphoinositide-dependent protein kinase 1
KW - Apoptosis
KW - Inositol polyphosphates
KW - Phosphoinositide 3-kinase
KW - Protein kinase B-Akt
UR - http://www.scopus.com/inward/record.url?scp=74249085433&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=74249085433&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6605408
DO - 10.1038/sj.bjc.6605408
M3 - Article
VL - 102
SP - 104
EP - 114
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 1
ER -