Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
Leukemia. 2010 Aug;24(8):1476-86. doi: 10.1038/leu.2010.117. Epub 2010 Jun 3.
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.
套细胞淋巴瘤（MCL）是一种侵袭性 B 细胞非霍奇金淋巴瘤，其特征是对常规化疗经常产生耐药性。在这项研究中，我们提供了证据表明，非诺贝特，作为过氧化物酶体增殖物激活受体-α（PPARα）的激动剂而广为人知，可通过诱导有效凋亡来治疗 MCL 细胞。在 72 小时内，将非诺贝特添加到 MCL 细胞系中，在大约 20μM 时可使活细胞数量减少 50%。细胞生长的减少归因于凋亡，这可通过 caspase 3 和多聚（ADP-核糖）聚合酶的裂解得到证明。GW6471（一种特异性 PPARα拮抗剂）对非诺贝特介导的作用没有明显影响。使用凋亡途径特异性寡核苷酸阵列，我们发现非诺贝特显著下调了几种促生存基因，包括肿瘤坏死因子-α（TNFα）。重要的是，添加重组 TNFα可部分抵抗非诺贝特诱导的凋亡。非诺贝特还降低了核因子（NF）-κB-p65 的核易位，并以剂量依赖性方式显著抑制 NF-κB 的 DNA 结合。总之，非诺贝特对 MCL 有效，其机制可归因于其对 TNFα/NF-κB 信号轴的抑制作用。鉴于非诺贝特在人类中的安全性已被记录在案，它可能为 MCL 患者提供有价值的治疗选择。
