Cytosolic Phospholipase A2: Targeting Cancer through the Tumor Vasculature

Purpose: In vascular endothelial cells, low doses of ionizing radiation trigger the immediate activation of cytosolic phospholipase A2 (cPLA(2)). This event initiates prosurvival signaling that could be responsible for radioresistance of tumor vasculature. Thus, the development of radiosensitizers targeting these survival pathways may enhance tumor response to radiation therapy. Arachidonyltrifluoromethyl Ketone (AACOCF(3)), a specific cPLA(2) inhibitor, was studied as a potential radiosensitizer. Experimental Design: Vascular endothelial cells (3 B11 and MPMEC) and lung tumor cells (LLC and H460) were treated with 1 mu mol/L AACOCF(3) for 30 minutes prior to irradiation. Treatment response was evaluated by clonogenic survival, activation of extracellular signal-regulated kinase 1/2 (ERK1/2), tubule formation, and migration assays. For in vivo experiments, mice with LLC or H460 tumors in the hind limbs were treated for 5 consecutive days with 10 mg/kg AACOCF(3) administered daily 30 minutes prior to irradiation. Treatment response was assessed by tumor growth delay, Power Doppler Sonography, and immunohistochemistry. Results: In cell culture experiments, inhibition of cPLA(2) with AACOCF(3) prevented radiation-induced activation of ERK1/2 and decreased clonogenic survival of irradiated vascular endothelial cells but not the lung tumor cells. Treatment with AACOCF(3) also attenuated tubule formation and migration in irradiated vascular endothelial cells. In both tumor mouse models, treatment with AACOCF(3) prior to irradiation significantly suppressed tumor growth and decreased overall tumor blood flow and vascularity. Increased apoptosis in both tumor cells and tumor vascular endothelium was determined as a possible mechanism of the observed effect. Conclusion: These findings identify cPLA(2) as a novel molecular target for tumor sensitization to radiation therapy through the tumor vasculature.