Potentiation of doxorubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models

Herath, Nirmitha I.; Devun, Flavien; Herbette, Aurélie; Lienafa, Marie-Christine; Chouteau, Philippe; Sun, Jian‐Sheng; Dutreix, Marie; Denys, Alban

doi:10.1007/s00330-017-4792-1

Cited by 12 publications

(12 citation statements)

References 40 publications

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“…The GO results indicated that the upregulated DEGs were primarily involved in the ‘daunorubicin metabolic process’ and ‘doxorubicin metabolic process’. Recent studies have demonstrated that daunorubicin interacts with lipid membrane mimetic models of cancer cells in general ( 30 ) and that doxorubicin efficacy is potentiated by the DNA repair inhibitor, DT01 in preclinical animal models of HCC ( 31 ). The enriched GO terms of the downregulated DEGs were primarily involved in ‘acute-phase response’, ‘monooxygenase activity’ and ‘iron ion binding’.…”

Section: Discussionmentioning

confidence: 99%

Role of CYP4F2 as a novel biomarker regulating malignant phenotypes of liver cancer cells via the Nrf2 signaling axis

et al. 2020

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Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancer worldwide. The present study attempted to identify a prognostic biomarker for HCC. RNA sequencing data from the GSE63863 dataset were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified based on a protein-protein interaction (PPI) network, and prognostic evaluation was subsequently conducted. Following lentiviral transfection, the migratory, proliferative and apoptotic abilities of cells were evaluated using wound healing, Cell Counting Kit-8, Transwell migration and apoptosis assays. A total of 192 DEGs were identified from 11 pairs of HCC and matched non-tumor samples. The PPI network revealed the top three modules, and eight genes were identified from these modules. The expression levels of cytochrome P450 family 4 subfamily F member 2 (CYP4F2) were downregulated in 50 HCC samples from The Cancer Genome Atlas and in the HCC Hep3B cell line. Low CYP4F2 expression was associated with a lower overall survival time. Functional studies revealed that CYP4F2 overexpression inhibited HCC cell proliferation and migration, and induced apoptosis. Furthermore, CYP4F2 overexpression repressed the expression of genes in the nuclear factor, erythroid 2 like 2 (Nrf2) signaling pathway, including Nrf2, heme oxygenase-1 and ferritin heavy chain 1, while increasing NAD(P)H quinone dehydrogenase 1 expression, suggesting that CYP4F2 overexpression reversed the antioxidant response of liver cancer cells. Overall, the present findings indicated that CYP4F2 may be a potential prognostic biomarker for predicting tumorigenesis and long-term survival rates in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

Role of CYP4F2 as a novel biomarker regulating malignant phenotypes of liver cancer cells via the Nrf2 signaling axis

et al. 2020

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“…The expected benefit of the combination of AsiDNA with CT is based on synergistic effect showed in non-clinical studies. [13][14][15] In a study using NCI-H446 cells, initially sensitive to carboplatin treated with or without AsiDNA, cell populations treated with both carboplatin (2.5 µM) (high dose corresponding to the IC90) and AsiDNA (low dose-2.5 µM) remained very sensitive to the drugs, while carboplatin resistance was observed in all cell populations treated with carboplatin alone after repeated cycles, demonstrating that AsiDNA, at a low sub-active dose, abrogated the emergence of acquired resistance to carboplatin. 15 In fact, by abrogating the DNA repair machinery, AsiDNA sensitises tumours to DNA-damaging agents like CT and RT.…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacological effect has been confirmed with different routes of administration (intratumoural [IT], intraperitoneal, intravenous [IV], subcutaneous [SC], intra-arterial) and with different treatment modalities: monotherapy, combination with radiotherapy (RT) and other locoregional treatment (i.e., radiofrequency ablation, transcatheter arterial chemoembolisation), various chemotherapy [CT] and PARPi. [13][14][15][16][17] AsiDNA was shown to induce cumulative antitumour activity with low probability of acquired resistance in preclinical models. 18 In the clinic, the drug was first investigated in 23 patients with skin metastases of melanoma in a Phase 1 dose-escalation study, 19 which evaluated the safety and pharmacokinetics (PK) of AsiDNA administered by SC (IT/ peri-tumoural) injections in combination with palliative RT.…”

Section: Introductionmentioning

confidence: 99%

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

et al. 2020

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Background AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. Methods The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. Results The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. Conclusion The dose of 600 mg was identified as the optimal dose for further clinical development. Clinical trial registration Clinical trial registration (NCT number): NCT03579628.

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“…Biau et al (2014) conducted a preclinical study in which a cholesterol-conjugated Dbait molecule, DT01, sensitized melanoma cells to radiotherapy both in vitro and in vivo [ 128 ]. In addition, DT01 has been shown to improve the efficacy of the chemotherapeutic doxorubicin in mouse models bearing hepatocellular carcinoma [ 130 ]. Herath et al (2016) investigated the chemosensitizing effects of DT01 in combination with a two-drug chemotherapeutic regimen (oxaliplatin and 5-fluorouracil) in an in vivo colorectal liver metastases model, and have reported significant anti-tumour effects using the combined treatment [ 131 ].…”

Section: Deoxyribonucleic Acid Repair Pathways As Therapeutic Tarmentioning

confidence: 99%

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

Helena

Joubert

Grobbelaar

et al. 2018

IJMS

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Deoxyribonucleic acid (DNA) is the self-replicating hereditary material that provides a blueprint which, in collaboration with environmental influences, produces a structural and functional phenotype. As DNA coordinates and directs differentiation, growth, survival, and reproduction, it is responsible for life and the continuation of our species. Genome integrity requires the maintenance of DNA stability for the correct preservation of genetic information. This is facilitated by accurate DNA replication and precise DNA repair. DNA damage may arise from a wide range of both endogenous and exogenous sources but may be repaired through highly specific mechanisms. The most common mechanisms include mismatch, base excision, nucleotide excision, and double-strand DNA (dsDNA) break repair. Concurrent with regulation of the cell cycle, these mechanisms are precisely executed to ensure full restoration of damaged DNA. Failure or inaccuracy in DNA repair contributes to genome instability and loss of genetic information which may lead to mutations resulting in disease or loss of life. A detailed understanding of the mechanisms of DNA damage and its repair provides insight into disease pathogeneses and may facilitate diagnosis and the development of targeted therapies.

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Potentiation of doxorubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models

Abstract: • DT01 combined with TACE leads to significant anti-tumour efficacy without additional toxicity. • A potential anti-angiogenic role of DT01 was identified in preclinical models. • DT01 may potentiate HCC treatment by enhancing the efficacy of TACE.

Cited by 12 publications

References 40 publications

Role of CYP4F2 as a novel biomarker regulating malignant phenotypes of liver cancer cells via the Nrf2 signaling axis

Role of CYP4F2 as a novel biomarker regulating malignant phenotypes of liver cancer cells via the Nrf2 signaling axis

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

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

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