15357163mct170405-sup-182919_2_supp_4189968_kvwnjn.png (272.08 kB)
Sup Figure S3 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 DutreixSup Figure S3. Micronuclei frequency but not doubling time nor AsiDNA cell uptake or activation of H2AX phosphorylation, are predictive biomarker for sensitivity to AsiDNA. Spearman correlation between AsiDNa efficiency (AsiDNA EC50, µM), and : (A) the AsiDNA uptake (Cy5.5-AsiDNA, MFI) ; (B) the LDL-receptor expressed at the cell membrane (LDL-R, MFI), and (C) the phosphorylation of H2AX histone variant (�-H2AX, MFI and �-H2AX, % positive respectively) and (D) Micronuclei frequency of the different cells lines (expressed as the percentage of cells with micronuclei) and (E) the cell lines doubling time (hours). P values are shown.
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CIFFRE-ANRT
Institut National du Cancer
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ARTICLE ABSTRACT
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.Usage metrics
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CarcinogenesisDNA damage and repairChemotherapyBiochemical modulators of the therapeutic indexCombination chemotherapyDrug MechanismsCellular responses to anticancer drugsModulation of DNA repairHematological CancersLeukemiasImmunologyImmunomodulationPharmacologyCellular pharmacologyRadiobiologyRadiation-induced DNA damageSmall Molecule Agents
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