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Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells

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 patient...

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Autores principales: Yamashita, Ken, Kiyonari, Shinichi, Tsubota, Shoma, Kishida, Satoshi, Sakai, Ryuichi, Kadomatsu, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385364/
https://www.ncbi.nlm.nih.gov/pubmed/32415892
http://dx.doi.org/10.1111/cas.14485
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author Yamashita, Ken
Kiyonari, Shinichi
Tsubota, Shoma
Kishida, Satoshi
Sakai, Ryuichi
Kadomatsu, Kenji
author_facet Yamashita, Ken
Kiyonari, Shinichi
Tsubota, Shoma
Kishida, Satoshi
Sakai, Ryuichi
Kadomatsu, Kenji
author_sort Yamashita, Ken
collection PubMed
description 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.
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spelling pubmed-73853642020-07-30 Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells Yamashita, Ken Kiyonari, Shinichi Tsubota, Shoma Kishida, Satoshi Sakai, Ryuichi Kadomatsu, Kenji Cancer Sci Original Articles 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. John Wiley and Sons Inc. 2020-06-10 2020-07 /pmc/articles/PMC7385364/ /pubmed/32415892 http://dx.doi.org/10.1111/cas.14485 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Yamashita, Ken
Kiyonari, Shinichi
Tsubota, Shoma
Kishida, Satoshi
Sakai, Ryuichi
Kadomatsu, Kenji
Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title_full Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title_fullStr Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title_full_unstemmed Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title_short Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN‐amplified neuroblastoma cells
title_sort thymidylate synthase inhibitor raltitrexed can induce high levels of dna damage in mycn‐amplified neuroblastoma cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385364/
https://www.ncbi.nlm.nih.gov/pubmed/32415892
http://dx.doi.org/10.1111/cas.14485
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