The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling.

Abstract

BACKGROUND:

The purpose of the study was to evaluate the use of phospho-Akt in mouse and human skin as a surrogate target for tumor phospho-Akt to measure the effect of antitumor inhibitors of phosphatidylinositol-3-kinase (PI-3-K)/Akt (protein kinase B) signaling.

METHOD:

The expression of phosphoSer473-Akt was quantitatively assessed by Western blotting in human HT-29 colon, MCF-7 breast, A-549 non small cell lung tumor xenografts in mice, and by immunohistochemistry in mouse skin and human hair.

RESULTS:

The pattern of PI-3-K isoforms in human hair keratinocytes was similar to that in tumor but mouse hair keratinocytes showed a different pattern. A high level of phospho-Akt staining was present in keratinocytes of the external root sheath of the hair and was inhibited by the PI-3-K inhibitor PX-866 administered to mice, and in human hair exposed to PX-866 in culture. The inhibition of phospho-Akt by PX-866 in mouse hair keratinocytes was greater than inhibition of phospho-Akt in HT-29 and A-549 xenografts in the same mice. Phospho-Akt in mouse hair keratinocytes was inhibited by the Akt inhibitor PX-316 to a lesser degree than in MCF-7 tumor xenografts.

CONCLUSIONS:

Hair offers a way of measuring the effects of PI-3-K signaling inhibitors and, in cancer patients, may provide a readily obtainable surrogate tissue for assessing PI-3-K and phospho-Akt inhibition in tumor.

• Authors: Ryan Williams, Amanda F Baker, Nathan T Ihle, Ashley R Winkler, Lynn Kirkpatrick, Garth Powis
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 58 Issue 4 Pg. 444-50 (Oct 2006) ISSN: 0344-5704 [Print] Germany
• PMID: 16485116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol
• Enzyme Inhibitors
• Gonanes
• Inositol Phosphates
• PX-866
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Gonanes (pharmacology)
• Hair (enzymology)
• Humans
• Inositol Phosphates (pharmacology)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Rabbits
• Signal Transduction (drug effects)
• Skin (enzymology)