INSERM, U866, Dijon, France.
Haematologica. 2012 Jan;97(1):38-46. doi: 10.3324/haematol.2011.046466. Epub 2011 Sep 20.
Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas.
Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis.
Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation.
We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.
非霍奇金氏 B 细胞淋巴瘤约占 B 细胞淋巴瘤的 70%。尽管其发病率在全球范围内显著增加，但由于常规疗法无效，该病仍与高发病率相关，因此迫切需要新的治疗方法。包括多酚和细胞因子 TRAIL 在内的非常规化合物，因其能够恢复包括淋巴瘤在内的大量肿瘤中的细胞凋亡而被广泛研究。
通过 Hoechst、流式细胞术、Western blot、qPCR、使用 siRNA 或线粒体途径的药理学抑制剂以及免疫沉淀和翻译后修饰分析，确定了 TRAIL 耐药和槲皮素在非霍奇金氏淋巴瘤细胞系中重新激活凋亡机制的分子机制。
结果表明，尽管由于染色体易位 t(14;18)导致 Bcl-2 表达水平高，但天然类黄酮槲皮素可恢复对耐药转化滤泡性淋巴瘤 B 细胞系的 TRAIL 诱导的细胞死亡。槲皮素通过诱导 Mcl-1 的蛋白酶体降解并抑制 survivin 在 mRNA 水平的表达来挽救线粒体的激活，而与 p53 无关。TRAIL 途径的恢复需要 Bax 和 Bak，但独立于增强的 TRAIL DISC 形成。
我们证明了槲皮素通过失活 survivin 和 Mcl-1 表达足以恢复耐药非霍奇金氏淋巴瘤 B 细胞对 TRAIL 的敏感性。因此，我们的研究结果表明，将槲皮素与 TRAIL 治疗联合使用可能对治疗非霍奇金氏淋巴瘤有用。
