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Leuk Lymphoma. 2017 Dec;58(12):2905-2915. doi: 10.1080/10428194.2017.1317091. Epub 2017 May 16.

Frondoside A induces AIF-associated caspase-independent apoptosis in Burkitt lymphoma cells.

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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.
c School of Natural Sciences , Far Eastern Federal University , Vladivostok , Russian Federation.
d Tumor and Breast Center ZeTuP , St. Gallen , Switzerland.


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.


AIF; Burkitt lymphoma; Marine glycoside; caspase-independent apoptosis; frondoside A

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