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The toxicity of nitrofuran compounds on melanoma and neuroblastoma cells is enhanced by Olaparib and ameliorated by melanin pigment.
- Source :
-
DNA repair [DNA Repair (Amst)] 2013 Nov; Vol. 12 (11), pp. 1000-6. Date of Electronic Publication: 2013 Sep 23. - Publication Year :
- 2013
-
Abstract
- Nitrofurans are commonly used for the treatment of trypanosomal diseases including Chagas disease. More recently, following the fortuitous discovery that nifurtimox was clinically active against neuroblastoma, nitrofuran compounds are being investigated for activity against cancer. Herein, we show that nitrofuran compounds are similarly potent to human malignant melanoma and neuroblastoma cells. Furthermore, a recently discovered nitrofuran compound, NFN1, was 50- to 175-fold more potent than nifurtimox against human melanoma and neuroblastoma cell lines. As nitrofuran compounds are known to act as pro-drugs, producing DNA-damaging reactive intermediates upon activation, we investigated the DNA repair pathways involved. We show that, contrary to research in Escherichia coli, the Nucleotide Excision Repair pathway is not required to repair nitrofuran-induced DNA damage in mammalian cells. Instead, we show that inhibiting repair of single-strand DNA breaks with the poly(ADP-ribose) polymerase (PARP) inhibitor, Olaparib, enhances nitrofuran toxicity in melanoma and neuroblastoma cells. We propose that this is due to mammalian cells utilising Type 2 nitroreductases for nitrofuran activation producing Reactive Oxygen Species which cause DNA damage that is repaired by the Single Strand Break Repair and/or Base Excision Repair pathways, whereas in bacteria and trypanosomes, Type 1 nitroreductases are also utilised resulting in different DNA lesions. In addition we show that, consistent with Reactive Oxygen Species being formed upon nitrofuran activation and the ability of melanin to absorb Reactive Oxygen Species, production of melanin in melanoma cells offers some protection from NFN1- and hydrogen peroxide-induced toxicity. Our data suggest that combinations of Olaparib and nitrofuran compounds may be advantageous for the treatment of melanoma and neuroblastoma, but that the protection offered to melanoma cells by their melanin pigment must be taken into account.<br /> (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Antineoplastic Combined Chemotherapy Protocols
Cell Line, Tumor
DNA Breaks, Single-Stranded drug effects
DNA Repair
Humans
Mice
Nitrofurans therapeutic use
Phthalazines therapeutic use
Piperazines therapeutic use
Poly(ADP-ribose) Polymerases genetics
Poly(ADP-ribose) Polymerases metabolism
Reactive Oxygen Species metabolism
Antineoplastic Agents pharmacology
Melanins metabolism
Melanoma drug therapy
Neuroblastoma drug therapy
Nitrofurans pharmacology
Phthalazines pharmacology
Piperazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1568-7856
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- DNA repair
- Publication Type :
- Academic Journal
- Accession number :
- 24070777
- Full Text :
- https://doi.org/10.1016/j.dnarep.2013.08.017