The toxicity of nitrofuran compounds on melanoma and neuroblastoma cells is enhanced by Olaparib and ameliorated by melanin pigment.
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.
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Ewan M
EM
McNeil
Ann-Marie
AM
Ritchie
David W
DW
Melton
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004260:DNA Repair; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy*; D009581:Nitrofurans / Q000494:pharmacology* / Q000627:therapeutic use; D010793:Phthalazines / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D008543:Melanins; D009581:Nitrofurans; D010793:Phthalazines; D010879:Piperazines; D017382:Reactive Oxygen Species; C041877:eumelanin; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
ERCC1-XPF; Melanin; Melanoma; Neuroblastoma; Nitrofuran; PARP inhibitor