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Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

ABSTRACT: The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates.

SUBMITTER: Murray J

PROVIDER: S-EPMC5665171 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

Murray Jayne J Valli Emanuele E Yu Denise M T DMT Truong Alan M AM Gifford Andrew J AJ Eden Georgina L GL Gamble Laura D LD Hanssen Kimberley M KM Flemming Claudia L CL Tan Alvin A Tivnan Amanda A Allan Sophie S Saletta Federica F Cheung Leanna L Ruhle Michelle M Schuetz John D JD Henderson Michelle J MJ Byrne Jennifer A JA Norris Murray D MD Haber Michelle M Fletcher Jamie I JI

European journal of cancer (Oxford, England : 1990) 20170720

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 str ...[more]

PMID: 28735070

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Project description:Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins.The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1-4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins.A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 ?M (95% CI 0.17-0.29 ?M) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 ?M (95% CI 5.9-7.8 ?M) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine.Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions.

Dataset Information

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

Publications

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

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