Journal
CANCER RESEARCH
Volume 74, Issue 23, Pages 7069-7078Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2043
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Funding
- Riley Memorial Association
- NIH [R01 HL062996, R01 CA134014, R21 ES020965, K22ES023850, U54 HL117798]
- Veteran's Administration Merit Award [5I01BX000853]
- American Institute for Cancer Research [09A062]
- ACSIRG [4185607]
- Showalter Research Trust Fund [4485602]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2013/00584-2]
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Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. (C)2014 AACR.
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