Dyshlovoy Sergey A, Rast Stefanie, Hauschild Jessica, Otte Katharina, Alsdorf Winfried H, Madanchi Ramin, Kalinin Vladimir I, Silchenko Alexandra S, Avilov Sergey A, Dierlamm Judith, Honecker Friedemann, Stonik Valentin A, Bokemeyer Carsten, von Amsberg Gunhild
a Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology , Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf , Hamburg , Germany.
b Laboratory of Marine Natural Products Chemistry , G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences , Vladivostok , Russian Federation.
Leuk Lymphoma. 2017 Dec;58(12):2905-2915. doi: 10.1080/10428194.2017.1317091. Epub 2017 May 16.
For patients with refractory or relapsed Burkitt lymphoma (BL), no standard therapy is available for second-line treatment to date. Nonfunctional caspases-dependent apoptosis pathways, inactivating p53 mutations and pro-survival autophagy prevent activity of conventional chemotherapy. Thus, new drugs bypassing these mechanisms of resistance are required. Here, we investigated the efficacy of the marine natural compound frondoside A (FrA) in eight BL cell lines. FrA revealed cytotoxic effects in all cell lines tested including the multiresistant CA46 cells. Remarkably, FrA induced caspases- and p53-independent apoptosis, which was characterized by decreased expression of antiapoptotic survivin and Bcl-2, mitochondria targeting (release of cytochrome C, HtrA2/Omi and the apoptosis-inducing factor (AIF), and altered production of ROS) and translocation of AIF to the nuclei. In addition, signs of inhibition of pro-survival autophagy were observed. Thus, FrA is a promising candidate for the treatment of refractory or relapsed BL revealing resistances to standard therapies.
对于难治性或复发性伯基特淋巴瘤（BL）患者，迄今为止尚无标准疗法用于二线治疗。非功能性半胱天冬酶依赖性凋亡途径、使p53失活的突变以及促生存自噬会阻碍传统化疗的活性。因此，需要能绕过这些耐药机制的新药。在此，我们研究了海洋天然化合物海参苷A（FrA）对8种BL细胞系的疗效。FrA在所有测试的细胞系中均显示出细胞毒性作用，包括多药耐药的CA46细胞。值得注意的是，FrA诱导了不依赖半胱天冬酶和p53的凋亡，其特征为抗凋亡蛋白survivin和Bcl-2的表达降低、线粒体靶向作用（细胞色素C、HtrA2/Omi和凋亡诱导因子（AIF）的释放）、活性氧生成改变以及AIF转位至细胞核。此外，还观察到了促生存自噬受到抑制的迹象。因此，FrA是治疗对标准疗法耐药的难治性或复发性BL的一个有前景的候选药物。
