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

Abstract

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.

Keywords:

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

Acknowledgments

This research (biological experiments) was supported by the Eppendorfer Krebs- und Leukämiehilfe e.V. is registered society in Hamburg, Germany with the register number VR 14656 Hamburg. SD was supported by a scholarship of the Department of Oncology, Hematology, Bone Marrow Transplantation with section Pneumology, Department of Medicine, University Hospital Hamburg-Eppendorf (20246, Martinistraße 52, 20251 Hamburg). This research (isolation and purification of FrA) was partially supported by the Grant 16-03-00553а from RFBR.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2017.1317091.

Additional information

Funding

This research (biological experiments) was supported by the Eppendorfer Krebs- und Leukämiehilfe e.V. is registered society in Hamburg, Germany with the register number VR 14656 Hamburg. SD was supported by a scholarship of the Department of Oncology, Hematology, Bone Marrow Transplantation with section Pneumology, Department of Medicine, University Hospital Hamburg-Eppendorf (20246, Martinistraße 52, 20251 Hamburg). This research (isolation and purification of FrA) was partially supported by the Grant 16-03-00553а from RFBR.