Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt

Joell Gills, Susan Holbeck, Melinda Hollingshead, Stephen M. Hewitt, Alan P. Kozikowski, Phillip A. Dennis

Research output: Contribution to journalArticle

Abstract

The serine/threonine kinase Akt is a promising target in cancer. We previously identified five phosphatidylinositol ether lipid analogues (PIA) that inhibited Akt activation and selectively killed lung and breast cancer cells with high levels of Akt activity. To assess the spectrum of activity in other cell types and to compare PIAs with other inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, we compared growth inhibition by PIAs against the PI3K inhibitors LY294002 and wortmannin and the mTOR inhibitor rapamycin in the NCI60 cell line panel. Although each of these compounds inhibited the growth of all the cell lines, distinct patterns were observed. The PIAs were the least potent but the most cytotoxic. The broad spectrum of activity of PIAs was confirmed in vivo in hollow fiber assays. The response to PIAs was significantly correlated with levels of active but not total Akt in the NCI60, as assessed using COMPARE analysis. However, a number of molecular targets were identified whose expression was more highly correlated with sensitivity to PIAs than active Akt. Expression of these molecular targets did not overlap with those that correlated with sensitivity to LY294002, wortmannin, or rapamycin. A COMPARE analysis of the National Cancer Institute chemical screening database revealed that the patterns of activity of PIAs correlated best with patterns of activity of other lipid-based compounds. These studies show that although PIAs are widely active in cancer cells, which correlates with the presence of its intended target, active Akt, PIAs are biologically distinct from other known inhibitors of the PI3K/Akt/mTOR pathway.

Original languageEnglish (US)
Pages (from-to)713-722
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Fingerprint

Sirolimus
Phosphatidylinositols
Ether
Phosphatidylinositol 3-Kinase
Lipids
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Chemical Databases
Cell Line
National Cancer Institute (U.S.)
Protein-Serine-Threonine Kinases
Growth
Lung Neoplasms
Neoplasms
Breast Neoplasms
wortmannin

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. / Gills, Joell; Holbeck, Susan; Hollingshead, Melinda; Hewitt, Stephen M.; Kozikowski, Alan P.; Dennis, Phillip A.

In: Molecular Cancer Therapeutics, Vol. 5, No. 3, 03.2006, p. 713-722.

Research output: Contribution to journalArticle

Gills, Joell ; Holbeck, Susan ; Hollingshead, Melinda ; Hewitt, Stephen M. ; Kozikowski, Alan P. ; Dennis, Phillip A. / Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 3. pp. 713-722.
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