In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316

Emmanuelle Meuillet, Nathan Ihle, Amanda F Baker, Jaime M. Gard, Chelsea Stamper, Ryan Williams, Amy Coon, Daruka Mahadevan, Benjamin L. George, Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo- inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3β, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)- trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-β- cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

Original languageEnglish (US)
Pages (from-to)513-527
Number of pages15
JournalOncology Research
Volume14
Issue number10
StatePublished - 2004

Fingerprint

Pharmacology
Phosphatidylinositols
Heterografts
Phosphatidylinositol 3-Kinase
Glycogen Synthase Kinase 3
Mitochondrial Genes
1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol
Protein-Serine-Threonine Kinases
Cyclodextrins
Gene Expression Profiling
Inositol
Hemolysis
Intravenous Administration
Colonic Neoplasms
Hydrogen
Neoplasms
Cell Survival
Down-Regulation
Phosphates
Phosphorylation

Keywords

  • Akt
  • Antitumor activity
  • D-3-Deoxy-phosphatidyl-myo-inositol ether lipid
  • Pharmacodynamics
  • PX-316

ASJC Scopus subject areas

  • Cancer Research

Cite this

Meuillet, E., Ihle, N., Baker, A. F., Gard, J. M., Stamper, C., Williams, R., ... Powis, G. (2004). In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncology Research, 14(10), 513-527.

In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. / Meuillet, Emmanuelle; Ihle, Nathan; Baker, Amanda F; Gard, Jaime M.; Stamper, Chelsea; Williams, Ryan; Coon, Amy; Mahadevan, Daruka; George, Benjamin L.; Kirkpatrick, Lynn; Powis, Garth.

In: Oncology Research, Vol. 14, No. 10, 2004, p. 513-527.

Research output: Contribution to journalArticle

Meuillet, E, Ihle, N, Baker, AF, Gard, JM, Stamper, C, Williams, R, Coon, A, Mahadevan, D, George, BL, Kirkpatrick, L & Powis, G 2004, 'In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316', Oncology Research, vol. 14, no. 10, pp. 513-527.
Meuillet, Emmanuelle ; Ihle, Nathan ; Baker, Amanda F ; Gard, Jaime M. ; Stamper, Chelsea ; Williams, Ryan ; Coon, Amy ; Mahadevan, Daruka ; George, Benjamin L. ; Kirkpatrick, Lynn ; Powis, Garth. / In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. In: Oncology Research. 2004 ; Vol. 14, No. 10. pp. 513-527.
@article{d0cd132764ba420ea365834c4cdb2cac,
title = "In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316",
abstract = "Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo- inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78{\%} at 10 h with recovery to 34{\%} at 48 h. Phosphorylation of GSK-3β, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)- trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20{\%} hydroxypropyl-β- cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.",
keywords = "Akt, Antitumor activity, D-3-Deoxy-phosphatidyl-myo-inositol ether lipid, Pharmacodynamics, PX-316",
author = "Emmanuelle Meuillet and Nathan Ihle and Baker, {Amanda F} and Gard, {Jaime M.} and Chelsea Stamper and Ryan Williams and Amy Coon and Daruka Mahadevan and George, {Benjamin L.} and Lynn Kirkpatrick and Garth Powis",
year = "2004",
language = "English (US)",
volume = "14",
pages = "513--527",
journal = "Oncology Research",
issn = "0965-0407",
publisher = "Cognizant Communication Corporation",
number = "10",

}

TY - JOUR

T1 - In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316

AU - Meuillet, Emmanuelle

AU - Ihle, Nathan

AU - Baker, Amanda F

AU - Gard, Jaime M.

AU - Stamper, Chelsea

AU - Williams, Ryan

AU - Coon, Amy

AU - Mahadevan, Daruka

AU - George, Benjamin L.

AU - Kirkpatrick, Lynn

AU - Powis, Garth

PY - 2004

Y1 - 2004

N2 - Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo- inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3β, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)- trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-β- cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

AB - Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo- inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3β, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)- trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-β- cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

KW - Akt

KW - Antitumor activity

KW - D-3-Deoxy-phosphatidyl-myo-inositol ether lipid

KW - Pharmacodynamics

KW - PX-316

UR - http://www.scopus.com/inward/record.url?scp=9244224608&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9244224608&partnerID=8YFLogxK

M3 - Article

C2 - 15559765

AN - SCOPUS:9244224608

VL - 14

SP - 513

EP - 527

JO - Oncology Research

JF - Oncology Research

SN - 0965-0407

IS - 10

ER -