Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis.
Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-alpha (PPARalpha), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 microM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARalpha antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-alpha (TNFalpha). Importantly, addition of recombinant TNF-alpha conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-kappaB-p65 and significantly inhibited the DNA binding of NF-kappaB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-alpha/NF-kappaB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.
Zak
Z
Z
Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
Gelebart
P
P
Lai
R
R
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D017931:DNA Primers; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D017931:DNA Primers; D016328:NF-kappa B; D047493:PPAR alpha; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; C006253:pirinixic acid; D011345:Fenofibrate