PMID- 32415892
OWN - NLM
STAT- MEDLINE
DCOM- 20200810
LR  - 20200810
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 111
IP  - 7
DP  - 2020 Jul
TI  - Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage 
      in MYCN-amplified neuroblastoma cells.
PG  - 2431-2439
LID - 10.1111/cas.14485 [doi]
AB  - 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.
CI  - (c) 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Yamashita, Ken
AU  - Yamashita K
AD  - Department of Biochemistry, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Kiyonari, Shinichi
AU  - Kiyonari S
AUID- ORCID: 0000-0002-4456-7186
AD  - Department of Biochemistry, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
AD  - Division of Biochemistry, Kitasato University School of Medicine, Sagamihara, 
      Japan.
FAU - Tsubota, Shoma
AU  - Tsubota S
AD  - Department of Biochemistry, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Kishida, Satoshi
AU  - Kishida S
AD  - Department of Biochemistry, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Sakai, Ryuichi
AU  - Sakai R
AD  - Division of Biochemistry, Kitasato University School of Medicine, Sagamihara, 
      Japan.
FAU - Kadomatsu, Kenji
AU  - Kadomatsu K
AD  - Department of Biochemistry, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
LA  - eng
GR  - JP15K18442/Japan Society for the Promotion of Science/
GR  - JP19K07711/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20200610
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (MYCN protein, human)
RN  - 0 (N-Myc Proto-Oncogene Protein)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - FCB9EGG971 (raltitrexed)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - *DNA Damage
MH  - Dose-Response Relationship, Drug
MH  - *Gene Amplification
MH  - Humans
MH  - Metabolic Networks and Pathways
MH  - N-Myc Proto-Oncogene Protein/*genetics
MH  - Neuroblastoma/*genetics/metabolism
MH  - Quinazolines/*pharmacology
MH  - Thiophenes/*pharmacology
MH  - Thymidylate Synthase/*antagonists & inhibitors
PMC - PMC7385364
OTO - NOTNLM
OT  - MYCN
OT  - antifolate
OT  - chemotherapy
OT  - neuroblastoma
OT  - raltitrexed
COIS- The authors have no conflict of interest.
EDAT- 2020/05/18 06:00
MHDA- 2020/08/11 06:00
PMCR- 2020/07/01
CRDT- 2020/05/17 06:00
PHST- 2020/03/05 00:00 [received]
PHST- 2020/05/02 00:00 [revised]
PHST- 2020/05/11 00:00 [accepted]
PHST- 2020/05/18 06:00 [pubmed]
PHST- 2020/08/11 06:00 [medline]
PHST- 2020/05/17 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - CAS14485 [pii]
AID - 10.1111/cas.14485 [doi]
PST - ppublish
SO  - Cancer Sci. 2020 Jul;111(7):2431-2439. doi: 10.1111/cas.14485. Epub 2020 Jun 10.