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Abstract

Introduction: Angiosarcomas are aggressive and malignant endothelial tumors. Several risk factors have been identified (eg. BRCA1/2 mutations, radiation, toxins and lymphedema), but pathological mechanisms remain unclear and the prognosis is poor. Fenofibrate is a hypolipidemic drug widely prescribed to treat dyslipidemia. It reduces LDL, vLDL, and triglycerides and increases HDL levels. The primary mechanism of fenofibrate action involves activation of the transcription factor PPARα, but other PPARα-independent mechanisms also exist. More recently, its efficacy as an anti-tumor drug has emerged. However, little is known about the endothelial actions of fenofibrate and whether these contribute to its anti-tumor properties. Here, we explore the actions of fenofibrate in endothelial cells that are capable of forming angiosarcomas in vivo. Methods: Mouse endothelial cells (MS1 VEGF; # CRL-2460) capable of inducing angiosarcoma were purchased from ATCC. These are primary mouse pancreatic islet cells that were transformed with temperature-sensitive SV40 large T antigen and screened for resistance with G418. The G418-selected immortalized cells were then retro-virally infected with a vector encoding primate VEGF. These cells have been shown to induce angiosarcomas in vivo in mice and are a good model system for studies of cancers, particularly angiosarcomas. Results: Incubation of MS1 VEGF cells with clinically relevant concentrations of fenofibrate (25-100 μM) strongly reduced their viability, with cell numbers reduced by approximately 10-fold after a 48h incubation with 50 μM fenofibrate {Cells/ml: ~1.8 million (control) versus ~0.2 million (50 μM fenofibrate)}. Morphologically, the cells were characterized by the appearance of perinuclear cytoplasmic vacuoles. In contrast, fenofibrate had a smaller effect on cell viability in primary human endothelial cells {Cells/ml: ~0.6 million (control) versus ~0.4 million (50 μM fenofibrate)}, thereby suggesting a relatively selective effect on MS1 VEGF cells. Hypothesizing that the effect of fenofibrate in these cells occurred through the induction of apoptosis, the effect of fenofibrate on the expression of proteins critical for cell survival and apoptosis was investigated biochemically. The data revealed down-regulation of the anti-apoptotic Bcl family protein Bcl-2 and the inhibitor of apoptosis protein survivin after treatment with fenofibrate. Fenofibrate treatment also decreased the expression of Akt and Erk proteins. In contrast, expression of Bcl-xl was relatively unaffected. Expression of the anti-diabetic hormone FGF-21 was detected in MS1 VEGF cells and this was also decreased after fenofibrate incubation. Conclusions: The data revealed a strong anti-proliferative action of fenofibrate in angiosarcoma-inducing endothelial cells but not primary human endothelial cells. These effects potentially occurred through regulation of proteins critical for cell survival and apoptosis. Future studies: Future investigations will focus on: (a) delineating the mechanisms involved (PPARα-dependent or -independent) (b) direct measurements of apoptosis by flow cytometry (c) the effect of fenofibrate on endothelial migration, invasion, proliferation, wound healing and tubule formation and (d) testing the possibility that fenofibrate acts by triggering changes in cellular calcium handling and (e) testing fenofibrate efficacy in angiosarcomas in vivo in mice. Key words: Apoptosis, Bcl-2, cancer, fenofibrate, FGF-21, survivin. This work was supported by a National Priorities Research Program grant (NPRP 6-428-3-113).

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/content/papers/10.5339/qfarc.2014.HBPP0064
2014-11-18
2019-11-17
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