Browsing by Author "Ferracini, Matheus"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor
    (American Association for Cancer Research, 2014-12-01) Sahu, Ravi P.; Ocana, Jesus A.; Harrison, Kathleen A.; Ferracini, Matheus; Touloukian, Christopher E.; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C.; Althouse, Sandra K.; Perkins, Susan M.; Speicher, Paul J.; Tyler, Douglas S.; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
    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.
  • Thumbnail Image
    Item
    Platelet-activating Factor-receptor agonists generated by chemotherapy thwart host anti-tumor immunity
    (Office of the Vice Chancellor for Research, 2014-04-11) Sahu, Ravi P; Ocana, Jesus A; Ferracini, Matheus; Touloukian, Christopher E; Konger, Raymond L; Travers, Jeffrey B
    Previous studies have established that pro-oxidative stressors suppress host immunity due to their ability to generate oxidized glycerophosphocholine (Ox-GPC) lipids with Platelet-activating Factor-receptor (PAF-R) agonist activity. Because many chemotherapeutic agents also induce reactive oxygen species, the present studies were designed to define if chemotherapeutic agents could thwart host anti-tumor immunity against melanoma via PAF-R activation. We demonstrate that treatment of melanoma cell lines in vitro and tumors in vivo with chemotherapeutic agents generates PAF-R-agonists in a process blocked by antioxidants, indicating the involvement of non-enzymatic PAF-R-agonists in this event. In a model system consisting of implantation of two tumors, we show that intratumoral chemotherapy with melphalan or etoposide of one tumor significantly augments the growth of the other (untreated) tumor in wild-type but not PAF-R-deficient hosts. Chemotherapeutic agents-mediated PAF-R-dependent increased tumor growth is blocked by systemic administration of antioxidants and cyclooxygenase-2 inhibitors. In addition, depleting antibodies against regulatory T cells (Tregs) significantly attenuated chemotherapy-mediated growth of untreated tumors, suggesting the role of Tregs in this process. Moreover, using FoxP3EGFP transgenic mice, we show that COX-2 inhibitor blocked intratumoral Tregs, indicating that Tregs are downstream to COX-2. Furthermore, PAF-R agonists were identified in perfusates of patients undergoing isolated limb chemoperfusion for melanoma with melphalan chemotherapy. Finally, various novel Ox-GPCs are identified after chemotherapy by mass spectrometry. These findings provide evidence for a novel and previously unappreciated pathway by which Ox-GPC PAF-R agonists produced as a by-product of chemotherapy modulate tumor growth via the inhibition of anti-tumor immunity. These studies might explain some instances of chemotherapy treatment failure and offer insights into potential therapeutic strategies that could enhance the overall anti-tumor effectiveness of chemotherapy.
  • Thumbnail Image
    Item
    Systemic Chemotherapy Is Modulated by Platelet-Activating Factor-Receptor Agonists
    (Hindawi Publishing Corporation, 2015-04-02) Sahu, Ravi P.; Ferracini, Matheus; Travers, Jeffrey B.; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Chemotherapy is used to treat numerous cancers including melanoma. However, its effectiveness in clinical settings is often hampered by various mechanisms. Previous studies have demonstrated that prooxidative stressor-mediated generation of oxidized lipids with platelet-activating factor-receptor (PAF-R) agonistic activity induces systemic immunosuppression that augments the growth of experimental melanoma tumors. We have recently shown that treatment of murine B16F10 melanoma cells in vitro or tumors implanted into syngeneic mice and treated intratumorally with various chemotherapeutic agents generated PAF-R agonists in a process blocked by antioxidants. Notably, these intratumoral chemotherapy-generated PAF-R agonists augmented the growth of secondary (untreated) tumors in a PAF-R dependent manner. As both localized and systemic chemotherapies are used based on tumor localization/stage and metastases, the current studies were sought to determine effects of PAF-R agonists on systemic chemotherapy against experimental melanoma. Here, we show that systemic chemotherapy with etoposide (ETOP) attenuates the growth of melanoma tumors when given subsequent to the tumor cell implantation. Importantly, this ETOP-mediated suppression of melanoma tumor growth was blocked by exogenous administration of a PAF-R agonist, CPAF. These findings indicate that PAF-R agonists not only negatively affect the ability of localized chemotherapy but also compromise the efficacy of systemic chemotherapy against murine melanoma.
  • Thumbnail Image
    Item
    Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands
    (Nature Publishing Group, 2015-01) Ferracini, Matheus; Sahu, Ravi P.; Harrison, Kathleen A.; Waeiss, Robert A.; Murphy, Robert C.; Jancar, Sonia; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine