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

Emmanuelle J. 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 Scopus citations

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
DOIs
StatePublished - 2004

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Meuillet, E. J., Ihle, N., Baker, A. F., Gard, J. M., Stamper, C., Williams, R., Coon, A., Mahadevan, D., George, B. L., Kirkpatrick, L., & Powis, G. (2004). In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncology Research, 14(10), 513-527. https://doi.org/10.3727/0965040042380487