Identification of MRP2 As a Targetable Factor Limiting Oxaliplatin Accumulation and Response in Gastrointestinal Cancer

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aut.relation.articlenumber2245en_NZ
aut.relation.endpage12
aut.relation.issue1en_NZ
aut.relation.journalScientific Reportsen_NZ
aut.relation.startpage1
aut.relation.volume9en_NZ
aut.researcherDrabsch, Julie
dc.contributor.authorMyint, Ken_NZ
dc.contributor.authorBiswas, Ren_NZ
dc.contributor.authorLi, Yen_NZ
dc.contributor.authorJong, Nen_NZ
dc.contributor.authorJamieson, Sen_NZ
dc.contributor.authorLiu, Jen_NZ
dc.contributor.authorHan, Cen_NZ
dc.contributor.authorSquire, Cen_NZ
dc.contributor.authorMerien, Fen_NZ
dc.contributor.authorLu, Jen_NZ
dc.contributor.authorNakanishi, Ten_NZ
dc.contributor.authorTamai, Ien_NZ
dc.contributor.authorMcKeage, Men_NZ
dc.date.accessioned2019-10-31T01:27:00Z
dc.date.available2019-10-31T01:27:00Z
dc.date.copyright2019en_NZ
dc.date.issued2019en_NZ
dc.description.abstractOxaliplatin 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.en_NZ
dc.identifier.citationScientific Reports, 9(1), 2245 (2019). doi:10.1038/s41598-019-38667-8
dc.identifier.doi10.1038/s41598-019-38667-8en_NZ
dc.identifier.issn2045-2322en_NZ
dc.identifier.issn2045-2322en_NZ
dc.identifier.urihttps://hdl.handle.net/10292/12949
dc.publisherNature Publishing Groupen_NZ
dc.relation.urihttps://www.nature.com/articles/s41598-019-38667-8
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.accessrightsOpenAccessen_NZ
dc.subjectCancer therapy; Gastrointestinal cancer
dc.titleIdentification of MRP2 As a Targetable Factor Limiting Oxaliplatin Accumulation and Response in Gastrointestinal Canceren_NZ
dc.typeJournal Article
pubs.elements-id354234
pubs.organisational-data/AUT
pubs.organisational-data/AUT/Health & Environmental Science
pubs.organisational-data/AUT/Health & Environmental Science/Applied Science
pubs.organisational-data/AUT/Health & Environmental Science/Interprofessional Health
pubs.organisational-data/AUT/Health & Environmental Science/School of Science
pubs.organisational-data/AUT/PBRF
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences/HA Science 2018 PBRF
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences/HI Interprofessional 2018 PBRF
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