title: Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung cancer animal models.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thotala
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craft
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ferraro
authors.forename: Rama P
authors.initials: RP
authors.lastname: Kotipatruni
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Bhave
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Jaboin
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001565:Benzoates; D004791:Enzyme Inhibitors; C586663:PLA-695; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D054510:Phospholipases A2, Cytosolic
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