Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN-amplified neuroblastoma cells.
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
DNA Damage
Dose-Response Relationship, Drug
Gene Amplification
Humans
Metabolic Networks and Pathways
N-Myc Proto-Oncogene Protein
/ genetics
Neuroblastoma
/ genetics
Quinazolines
/ pharmacology
Thiophenes
/ pharmacology
Thymidylate Synthase
/ antagonists & inhibitors
MYCN
antifolate
chemotherapy
neuroblastoma
raltitrexed
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
05
03
2020
revised:
02
05
2020
accepted:
11
05
2020
pubmed:
18
5
2020
medline:
11
8
2020
entrez:
17
5
2020
Statut:
ppublish
Résumé
MYCN gene amplification is consistently associated with poor prognosis in patients with neuroblastoma, a pediatric tumor arising from the sympathetic nervous system. Conventional anticancer drugs, such as alkylating agents and platinum compounds, have been used for the treatment of high-risk patients with MYCN-amplified neuroblastoma, whereas molecule-targeting drugs have not yet been approved. Therefore, the development of a safe and effective therapeutic approach is highly desired. Although thymidylate synthase inhibitors are widely used for colorectal and gastric cancers, their usefulness in neuroblastoma has not been well studied. Here, we investigated the efficacies of approved antifolates, methotrexate, pemetrexed, and raltitrexed (RTX), on MYCN-amplified and nonamplified neuroblastoma cell lines. Cell growth-inhibitory assay revealed that RTX showed a superior inhibitory activity against MYCN-amplified cell lines. We found no significant differences in the protein expression levels of the antifolate transporter or thymidylate synthase, a primary target of RTX, among the cell lines. Because thymidine supplementation could rescue the RTX-induced cell growth suppression, the effect of RTX was mainly due to the reduction in dTTP synthesis. Interestingly, RTX treatments induced single-stranded DNA damage response in MYCN-amplified cells to a greater extent than in the nonamplified cells. We propose that the high DNA replication stress and elevated levels of DNA damage, which are a result of deregulated expression of MYCN target genes, could be the cause of increased sensitivity to RTX.
Identifiants
pubmed: 32415892
doi: 10.1111/cas.14485
pmc: PMC7385364
doi:
Substances chimiques
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Quinazolines
0
Thiophenes
0
Thymidylate Synthase
EC 2.1.1.45
raltitrexed
FCB9EGG971
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2431-2439Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP15K18442
Organisme : Japan Society for the Promotion of Science
ID : JP19K07711
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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