Journal
ONCOLOGY RESEARCH
Volume 14, Issue 10, Pages 513-527Publisher
COGNIZANT COMMUNICATION CORP
DOI: 10.3727/0965040042380487
Keywords
PX-316; D-3-deoxy-phosphatidyl-myo-inositol ether lipid; Akt; antitumor activity; pharmacodynamics
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Funding
- NCI NIH HHS [CA52995, CA90821] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [U01CA052995, U54CA090821, U19CA052995] Funding Source: NIH RePORTER
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Akt, a serine/threoriine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (Ptdlns)-3-phosphates formed by Ptdlns-3-kinase. D-3Deoxy-phosphatidyl-myo-inositols that cannot be phosphorylated on the 3-position of the myo-mositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositoI I[(R)-2-methoxy-3-octadecyloxypropyI 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-3beta, a downstream target of Akt, is also inhibited. There is no decrease in Ptdlns(3,4,5)-trisphosphate levels by PX-316, showing it is not an inhibitor of Ptdlns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the Ptdlns-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-beta-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.
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