American Association for Cancer Research
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Sup Figure S4 from The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood

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posted on 2023-04-03, 14:47 authored by Sylvain Thierry, Wael Jdey, Solana Alculumbre, Vassili Soumelis, Patricia Noguiez-Hellin, Marie Dutreix

Sup Figure S4. Survival of malignant hematologic and normal human primary immune cells in response to AsiDNA dose escalation in combination with Etoposide: Cell survival was determined by MTT assay after four days of treatment. Data are presented as the association of AsiDNA on Etoposide efficiency (blue), the effect of Etoposide on AsiDNA efficiency (red), and the isobolograms of this association at the half maximal effective concentration of the two treatments (black). The envelope of additivity calculated from single treatments data is indicated by the dotted black line.



Institut National du Cancer



Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are a promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and platinum salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1, and U-937) and in normal primary human PBMCs, resting or activated T cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation, or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide-range drug with the potential to specifically increase DNA-damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation. Mol Cancer Ther; 16(12); 2817–27. ©2017 AACR.