Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 02 2019
19 02 2019
Historique:
received:
30
08
2018
accepted:
21
12
2018
entrez:
21
2
2019
pubmed:
21
2
2019
medline:
4
9
2020
Statut:
epublish
Résumé
Oxaliplatin is important for the clinical treatment of colorectal cancer and other gastrointestinal malignancies, but tumour resistance is limiting. Several oxaliplatin transporters were previously identified but their relative contributions to determining oxaliplatin tumour responses and gastrointestinal tumour cell sensitivity to oxaliplatin remains unclear. We studied clinical associations between tumour expression of oxaliplatin transporter candidate genes and patient response to oxaliplatin, then experimentally verified associations found with MRP2 in models of human gastrointestinal cancer. Among 18 oxaliplatin transporter candidate genes, MRP2 was the only one to be differentially expressed in the tumours of colorectal cancer patients who did or did not respond to FOLFOX chemotherapy. Over-expression of MRP2 (endogenously in HepG2 and PANC-1 cells, or induced by stable transfection of HEK293 cells) decreased oxaliplatin accumulation and cytotoxicity but those deficits were reversed by inhibition of MRP2 with myricetin or siRNA knockdown. Mice bearing subcutaneous HepG2 tumour xenografts were sensitised to oxaliplatin antitumour activity by concurrent myricetin treatment with little or no increase in toxicity. In conclusion, MRP2 limits oxaliplatin accumulation and response in human gastrointestinal cancer. Screening tumour MRP2 expression levels, to select patients for treatment with oxaliplatin-based chemotherapy alone or in combination with a MRP2 inhibitor, could improve treatment outcomes.
Identifiants
pubmed: 30783141
doi: 10.1038/s41598-019-38667-8
pii: 10.1038/s41598-019-38667-8
pmc: PMC6381153
doi:
Substances chimiques
ABCC2 protein, human
0
Multidrug Resistance-Associated Protein 2
0
Multidrug Resistance-Associated Proteins
0
Neoplasm Proteins
0
Oxaliplatin
04ZR38536J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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