Factors That Influence Fenofibrate Effects On Cancer Cells - Factors That Influence Fenofibrate Effects On Cancer Cells - Open Access Pub

DOI 10.14302/issn.2372-6601.jhor-13-362 A recent clinical trial for pediatric embryonal brain tumors reported encouraging results, with a treatment scheme that included peroxisome proliferator-activated receptor-α (PPARα) agonist fenofibrate 1. The treatment scheme was aimed at inhibiting neovascularization; however, the drugs used can inhibit cancer cell growth by a number of mechanisms. In a different treatment scheme, aimed to treat a variety of recurrent or progressive tumors, fenofibrate could not demonstrate similarly encouraging effects 2.Under which conditions can fenofibrate be effective? In basic and clinical research, PPAR agonists are generally used to inhibit angiogenesis 1, 2, 3. However, it has been revealed that they can stimulate angiogenesis as well, using as models human cultured endothelial cells and mouse cornea 4. It could be argued that cell type and microenvironment determine effects on angiogenesis, and can be determined by the cell and host composition of the preclinical study model. Downstream targets of PPAR agonists can have multiple effects on gene expression and cell physiology: The subject of PPAR ligands as anticancer drugs has been reviewed recently. Grabacka et al., note that PPARα activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α 5 which could explain, at least in part, the encouraging results of the Peyrl et al., study (more on this topic in 6). In cultured cervical cancer cells, however, fenofibrate can induce mRNA for PPARα, PPARγ and superoxide dismutase 1, with tendency to decrease radiation sensitivity 7. In different types of gastrointestinal cancer, PPAR activity above or below normal can affect tumor growth 8. High PPAR activity can kill cancer cells that are unable to utilize fatty acids as a source of energy, or that depend on signals mediated by transcription factors NF-kB or STAT3; on the other hand PPAR activity can support growth of cancer cells that are deficient in tumor suppressors such as APC, or cancer cells that derive energy from oxidation of fatty acids 8. Interestingly, in a recent mechanistic study on chronic lymphocytic leukemia (CLL), inhibitors of PPARα and fatty acid oxidation enzymes increased glucocorticoid-mediated killing of CLL cells in culture. The study authors noted a similar effect on mouse CLL xenografts, where immune-deficient mice could be rescued by combination of GCs and PPARα inhibition 9. CLL cells may use fatty acids as a source of energy, because they express lipoprotein lipase: palmitate oxidation rates in circulating CLL cells can be similar to