The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood

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. .

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…In addition, synergy between AsiDNA and conventional cancer therapies (etoposide, cyclophosphamide and radiotherapy) has been shown in 8 out of 10 lines of lymphoma and leukemia cell line. Moreover, AsiDNA increases DNA-damaging agent sensitivity of tumor cells without affecting normal hematological white blood cells [42]. These results are promising and AsiDNA is currently tested on phase I clinical trial as a monotherapy in advanced solid tumor.…”

Deoxyribonucleic Acid Damage and Repair: Capitalizing on Our Understanding of the Mechanisms of Maintaining Genomic Integrity for Therapeutic Purposes

“…Moreover, H2AX phosphorylation by DNA-PK was exclusive to tumour cells, thus indicating sparing of surrounding non-tumourigenic tissue [ 131 ]. A signal-interfering DNA (AsiDNA), which is a cholesterol-conjugated member of the Dbait family, induces preferential toxicity towards tumourigenic tissue whilst sparing non-tumourigenic hematologic cells and preserving immune function [ 132 ]. Thierry et al (2017) reported the induction of necrotic and apoptotic cell death by AsiDNA through p53-independent mechanisms in several lymphoma and leukaemia cell lines [ 132 ].…”

“…A signal-interfering DNA (AsiDNA), which is a cholesterol-conjugated member of the Dbait family, induces preferential toxicity towards tumourigenic tissue whilst sparing non-tumourigenic hematologic cells and preserving immune function [ 132 ]. Thierry et al (2017) reported the induction of necrotic and apoptotic cell death by AsiDNA through p53-independent mechanisms in several lymphoma and leukaemia cell lines [ 132 ]. AsiDNA enters cells through low density lipoprotein (LDL) receptors and subsequently activates DNA-PK [ 132 ].…”

“…Thierry et al (2017) reported the induction of necrotic and apoptotic cell death by AsiDNA through p53-independent mechanisms in several lymphoma and leukaemia cell lines [ 132 ]. AsiDNA enters cells through low density lipoprotein (LDL) receptors and subsequently activates DNA-PK [ 132 ]. Dbait molecules improve the clinical outcomes of chemo- and radiotherapy by disturbing DNA repair processes in treated tumour tissue [ 128 , 132 , 133 ].…”

Targeting DNA Repair Pathways in Hematological Malignancies

“…Hematological malignancies (HM) account for approximately 10% of all newly diagnosed cancers and are usually characterized by genetic defect in the form of chromosomal translocation or breakpoint/fusion [ 4 ]. Many HM run a chronic relapsing course, culminating in therapy resistance with multiple lines of therapy [ 5 ]. Development of resistance to DNA-damaging chemotherapy agents such as cisplatin, cyclophosphamide, chlorambucil, and temozolomide can be somewhat mitigated with concurrent inhibition of DNA repair pathways, increasing cytotoxicity [ 6 ] and hence therapeutic efficacy [ 7 ].…”