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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Res 2014 ; 74 (23): 7069-78 Nephropedia Template TP
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Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor #MMPMID25304264
Sahu RP; Ocana JA; Harrison KA; Ferracini M; Touloukian CE; Al-Hassani M; Sun L; Loesch M; Murphy RC; Althouse SK; Perkins SM; Speicher PJ; Tyler DS; Konger RL; Travers JB
Cancer Res 2014[Dec]; 74 (23): 7069-78 PMID25304264show ga
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 non-enzymatically. 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 cyclooxygenase-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Further, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.