Combined Effects of Cytokine Trail-Based DR5-Specific Fusion Protein with Olaparib on Tumor Cell Lines with Different BRCA Mutation Status

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Abstract

Tumor cell death induction via activation of TRAIL (tumor necrosis factor-related apoptosis inducing ligand) cytokine signaling pathway is a promising strategy for anticancer therapy. Previously, we developed a fusion protein SRH-DR5-B-iRGD based on the DR5 (death receptor 5)-specific cytokine TRAIL variant DR5-B with antiangiogenic peptides. The SRH peptide specifically binds to the VEGFR2 (vascular endothelial growth factor receptor 2) receptor and blocks its VEGF-mediated activation; the iRGD peptide binds to integrin avP3 and the NRP-1 (neuropilin-1) receptor. All of these targets are known to be overexpressed on the surface of tumor cells. In the current study, we investigated the cytotoxic activity of the SRH-DR5-B-iRGD fusion protein in comparison with DR5-B in vitro in ovarian and breast adenocarcinoma cell lines with different BRCA mutation status in combination with a targeted poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Olaparib synergistically enhanced the cytotoxicity of TRAIL-based proteins regardless of the presence of BRCA mutations in the cells, and this effect was more pronounced for SRH-DR5-B-iRGD. Thus, the combination of SRH-DR5-B-iRGD with olaparib can be considered as a new approach to treatment of ovarian and breast adenocarcinomas regardless of the presence of BRCA mutations.

About the authors

A. V. Yagolovich

Faculty of Biology, Lomonosov Moscow State University

Email: yagolovichav@my.msu.ru
Moscow, 119234 Russia

A. A. Isakova

Faculty of Biology, Lomonosov Moscow State University; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Moscow, 119234 Russia; Moscow, 117997 Russia

E. V. Kukovyakina

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Moscow, 117997 Russia

D. A. Dolgikh

Faculty of Biology, Lomonosov Moscow State University; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Moscow, 119234 Russia; Moscow, 117997 Russia

M. P. Kirpichnikov

Faculty of Biology, Lomonosov Moscow State University; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Moscow, 119234 Russia; Moscow, 117997 Russia

M. E. Gasparian

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Moscow, 117997 Russia

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