PMID- 23894523
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 7
DP  - 2013
TI  - Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung 
      cancer animal models.
PG  - e69688
LID - 10.1371/journal.pone.0069688 [doi]
LID - e69688
AB  - Lung cancer remains the leading cause of cancer deaths in the United States and 
      the rest of the world. The advent of molecularly directed therapies holds promise 
      for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2) is 
      associated with tumor progression and radioresistance in mouse tumor models. 
      Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition 
      radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment 
      with PLA-695 attenuated radiation induced increases of phospho-ERK and 
      phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with 
      endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed 
      radiosensitization. PLA-695 in combination with irradiation (IR) significantly 
      reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and 
      induced cell death and attenuated invasion by tumor cells (LLC &A549). In a 
      heterotopic tumor model, the combination of PLA-695 and radiation delayed growth 
      in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of 
      PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold 
      model of LLC tumors, inhibition of cPLA2 in combination with radiation led to 
      enhanced destruction of tumor blood vessels. The anti-angiogenic effects of 
      PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of 
      NSCLC suggest that clinical trials for its capacity to improve radiotherapy 
      outcomes are warranted.
FAU - Thotala, Dinesh
AU  - Thotala D
AD  - Department of Radiation Oncology, Washington University in St. Louis, St. Louis, 
      Missouri, United States of America.
FAU - Craft, Jeffrey M
AU  - Craft JM
FAU - Ferraro, Daniel J
AU  - Ferraro DJ
FAU - Kotipatruni, Rama P
AU  - Kotipatruni RP
FAU - Bhave, Sandeep R
AU  - Bhave SR
FAU - Jaboin, Jerry J
AU  - Jaboin JJ
FAU - Hallahan, Dennis E
AU  - Hallahan DE
LA  - eng
GR  - R01-CA12575706/CA/NCI NIH HHS/United States
GR  - R01-CA14022002/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130719
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Benzoates)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (PLA-695)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Sulfonamides)
RN  - EC 3.1.1.4 (Phospholipases A2, Cytosolic)
SB  - IM
MH  - Animals
MH  - Benzoates/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*enzymology
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects/radiation effects
MH  - Cell Proliferation/drug effects/radiation effects
MH  - Cell Survival/drug effects/radiation effects
MH  - Disease Models, Animal
MH  - Endothelial Cells/drug effects/metabolism/radiation effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Lung Neoplasms/*enzymology/pathology/radiotherapy
MH  - Mice
MH  - Neovascularization, Pathologic/drug therapy/radiotherapy
MH  - Phospholipases A2, Cytosolic/*antagonists & inhibitors
MH  - Radiation, Ionizing
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Signal Transduction/drug effects/radiation effects
MH  - Sulfonamides/*pharmacology
MH  - Tumor Burden/drug effects/radiation effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC3716600
COIS- Competing Interests: PLA-695 was obtained from Pfizer Inc. under the 
      Pfizer-Washington University biomedical agreement. As per the Pfizer-Washington 
      University biomedical agreement the manuscript was submitted to Pfizer Inc. and 
      cleared for publication. Neither the authors nor any of their family members have 
      any financial or non financial competing interests with PLA-695 or Pfizer Inc. 
      The authors also confirm that this does not alter and adheres to all the PLOS ONE 
      policies on sharing data and materials.
EDAT- 2013/07/31 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/07/19
CRDT- 2013/07/30 06:00
PHST- 2012/10/31 00:00 [received]
PHST- 2013/06/14 00:00 [accepted]
PHST- 2013/07/30 06:00 [entrez]
PHST- 2013/07/31 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/07/19 00:00 [pmc-release]
AID - PONE-D-12-33989 [pii]
AID - 10.1371/journal.pone.0069688 [doi]
PST - epublish
SO  - PLoS One. 2013 Jul 19;8(7):e69688. doi: 10.1371/journal.pone.0069688. Print 2013.