PMID- 22452803
OWN - NLM
STAT- MEDLINE
DCOM- 20120808
LR  - 20220318
IS  - 1748-717X (Electronic)
IS  - 1748-717X (Linking)
VI  - 7
DP  - 2012 Mar 27
TI  - NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of 
      rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity.
PG  - 48
LID - 10.1186/1748-717X-7-48 [doi]
AB  - BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in 
      tumor cells and promotes tumor cell survival after radiation-induced DNA damage. 
      Because the pathway may not be completely inhibited after blockade of PI3K 
      itself, due to feedback through mammalian target of rapamycin (mTOR), more 
      effective inhibition might be expected by targeting both PI3K and mTOR 
      inhibition. MATERIALS AND METHODS: We investigated the effect of two dual 
      PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on 
      SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR 
      overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on 
      endothelial cells. Analysis of target protein phosphorylation, clonogenic 
      survival, number of residual gammaH2AX foci, cell cycle and apoptosis after radiation 
      was performed in both tumor and endothelial cells. In vitro angiogenesis assays 
      were conducted as well. RESULTS: Both compounds effectively inhibited 
      phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic 
      survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by 
      increased number of gammaH2AX foci, was detected after irradiation in the presence of 
      PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with 
      one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after 
      irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 
      blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing 
      in human umbilical venous endothelial cells (HUVEC) and human dermal 
      microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell 
      migration and capillary tube formation in vitro and enhanced the antivascular 
      effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis 
      in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both 
      tumor and endothelial all cells tumor. CONCLUSIONS: The results of this study 
      demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in 
      tumor and endothelial cells and may be of benefit when combined with 
      radiotherapy.
FAU - Fokas, Emmanouil
AU  - Fokas E
AD  - Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, UK.
FAU - Yoshimura, Michio
AU  - Yoshimura M
FAU - Prevo, Remko
AU  - Prevo R
FAU - Higgins, Geoff
AU  - Higgins G
FAU - Hackl, Wolfgang
AU  - Hackl W
FAU - Maira, Sauveur-Michel
AU  - Maira SM
FAU - Bernhard, Eric J
AU  - Bernhard EJ
FAU - McKenna, W Gillies
AU  - McKenna WG
FAU - Muschel, Ruth J
AU  - Muschel RJ
LA  - eng
GR  - 11563/CRUK_/Cancer Research UK/United Kingdom
GR  - 13092/CRUK_/Cancer Research UK/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120327
PL  - England
TA  - Radiat Oncol
JT  - Radiation oncology (London, England)
JID - 101265111
RN  - 0 
      (8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Cell Line, Tumor
MH  - Endothelial Cells/drug effects
MH  - Human Umbilical Vein Endothelial Cells/drug effects
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Quinolines/*pharmacology
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
PMC - PMC3348043
EDAT- 2012/03/29 06:00
MHDA- 2012/08/09 06:00
PMCR- 2012/03/27
CRDT- 2012/03/29 06:00
PHST- 2011/10/27 00:00 [received]
PHST- 2012/03/27 00:00 [accepted]
PHST- 2012/03/29 06:00 [entrez]
PHST- 2012/03/29 06:00 [pubmed]
PHST- 2012/08/09 06:00 [medline]
PHST- 2012/03/27 00:00 [pmc-release]
AID - 1748-717X-7-48 [pii]
AID - 10.1186/1748-717X-7-48 [doi]
PST - epublish
SO  - Radiat Oncol. 2012 Mar 27;7:48. doi: 10.1186/1748-717X-7-48.