Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt.
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.
Gills
Joell J
JJ
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
Holbeck
Susan
S
Hollingshead
Melinda
M
Hewitt
Stephen M
SM
Kozikowski
Alan P
AP
Dennis
Phillip A
PA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt