Fenofibrate triggers apoptosis of glioblastoma cells in vitro: new insights for therapy.

Fenofibrate, a peroxisome proliferator-activated receptor (PPARα) agonist, is a member of the fibrate class of anti-hyperlipidemic agents and has been widely used in the treatment of different forms of hyperlipidemia and hypercholesterolemia. PPARa is a ligand-inducible transcription factor that belongs to the nuclear-hormone-receptor family and mediates peroxisome proliferation action. Interestingly, growing evidence has indicated that PPARa agonist fenofibrate exerts anticancer properties, probably because of its anti-proliferative and pro-apoptotic activities, and, importantly, exhibits low systemic toxicity. However, it is not clear what role PPARa plays in the antiproliferative effect of fenofibrate, and the possibility of a PPARa-independent action is being considered. With respect to these mechanisms, in a recent issue of Cell Cycle, Wilk, et al. investigated the effect of fenofibrate treatment on the proliferative features of glioblastoma cells. Approximately, 50% of all primary brain tumors originate from glial cells, and glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Currently, the treatment of glioblastomas remains palliative and includes surgery, radiotherapy, chemotherapy and treatment with inhibitors and antibodies, which have been shown to prolong quality survival.

In their study, Wilk, et al. show that fenofibrate can effectively induce growth arrest and trigger apoptosis of glial tumor cells in a dose- and time-dependent manner. Interestingly, the authors observed that fenofibrate-induced apoptosis was preceded by nuclear accumulation and serine phosphorylation of the transcription factor FoxO3A as well as by FoxO-dependent expression of the pro-apoptotic protein Bim. In addition, the authors observed that other agonists of PPARa were less effective in changing cell viability with respect to fenofibrate, and that PPARα silencing by siRNA only partially rescued glioblastoma cells from the treatment, suggesting that both PPARa-dependent and -independent mechanisms may play a role in the fenofibrate-induced activation of FoxO3A and Bim, which, in turn, triggers apoptosis.

Different studies have reported that deregulation of the p16Ink4a-Cdk4-Rb cell cycle-controlling pathway is a common event in patients with GBM., It would be very interesting to investigate the impact of fenofibrate treatment on p16-Cdk4/6-Rb axis and its relationship with apoptosis triggering and cytotoxicity effects in glioblastoma cells. Not all glioblastomas have the same biological abnormalities, and this may be the reason why different patients respond differently to the same treatment, and why different patients with the same tumor type have different outcomes. In this context, it would be interesting to disclose the pleiotropic effects of fenofibrate on cell growth and death signaling and to determine if the response to this drug could be critically determined by p16Ink4a-Cdk4-Rb status in glioblastoma cells. Wilk, et al.’s study provides evidence that fenofibrate treatment can effectively trigger apoptosis via FoxO3A in glioblastoma cells, and this information may represent the first step in elucidating the anticancer effect(s) of this drug. Further studies are necessary to evaluate the impact of fenofibrate treatment in modulating cellular growth and death signaling of glioblastoma cells and to shed light on how the use of this drug may improve current anticancer therapies.