PMID- 16546986
OWN - NLM
STAT- MEDLINE
DCOM- 20060526
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 5
IP  - 3
DP  - 2006 Mar
TI  - Spectrum of activity and molecular correlates of response to phosphatidylinositol 
      ether lipid analogues, novel lipid-based inhibitors of Akt.
PG  - 713-22
AB  - 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.
FAU - Gills, Joell J
AU  - Gills JJ
AD  - Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
FAU - Holbeck, Susan
AU  - Holbeck S
FAU - Hollingshead, Melinda
AU  - Hollingshead M
FAU - Hewitt, Stephen M
AU  - Hewitt SM
FAU - Kozikowski, Alan P
AU  - Kozikowski AP
FAU - Dennis, Phillip A
AU  - Dennis PA
LA  - eng
GR  - N01-CO-12400/CO/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphatidylinositol Phosphates)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Chromones/pharmacology
MH  - Humans
MH  - Morpholines/pharmacology
MH  - Neoplasms/*drug therapy/enzymology
MH  - Phosphatidylinositol Phosphates/chemistry/pharmacology/*therapeutic use
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/chemistry/pharmacology/*therapeutic use
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors
EDAT- 2006/03/21 09:00
MHDA- 2006/05/27 09:00
CRDT- 2006/03/21 09:00
PHST- 2006/03/21 09:00 [pubmed]
PHST- 2006/05/27 09:00 [medline]
PHST- 2006/03/21 09:00 [entrez]
AID - 5/3/713 [pii]
AID - 10.1158/1535-7163.MCT-05-0484 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2006 Mar;5(3):713-22. doi: 10.1158/1535-7163.MCT-05-0484.