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Novel tetrahydroisoquinolin-ethyl-phenylamine based multidrug resistance inhibitors with broad-spectrum modulating properties

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Abstract

Purpose: The ATP-binding cassette transporters P-glycoprotein (Pgp) and BCRP are implicated in multidrug resistance (MDR) of many tumors. Multi-targeted inhibitors such as cyclosporin A, have been shown to circumvent MDR in clinical trials. Here, we present the characterization of a novel class of effective and multi-targeted tetrahydroisoquinolin-ethyl-phenylamine based MDR inhibitors. Methods: The novel MDR inhibitors, XR9577, WK-X-34, WK-X-50 and WK-X-84 were examined for cellular toxicity in several cell lines. Chemosensitivity and inhibition of BCRP-mediated mitoxantrone efflux were analyzed in BCRP-overexpressing MCF7/mx cells. Chemosensitivity towards daunorubicin and inhibition of Pgp-mediated efflux of 99mTc-Sestamibi were examined in Pgp-overexpressing A2780/Adr cells. Potential MRP-interactions were evaluated with 5-CFDA efflux assays in selectively transfected MRP-1, -2 and -3 cell lines. Results: All WK-X-compounds showed significant BCRP inhibition in the MCF7/mx cells resulting in significant increases in mitoxantrone intracellular accumulation and 200–300 fold increases in mitroxantrone cytotoxicity. WK-X-34 and XR9577 were also potent inhibitors of Pgp, increasing 99mTc-Sestamibi accumulation with IC50 values in the nM range. Daunorubicin cytotoxicity was also increased seven to eight-fold in cells co-treated with XR9577 or WK-X-34 (10 μM). These compounds did not appear to interact with the MRP transporters. As compared to cyclosporin A, these compounds showed reduced cellular toxicity and increased potency of BCRP and Pgp inhibition. Conclusion: The novel MDR inhibitors WK-X-34 and XR9577 demonstrate superior effectiveness in Pgp and BCRP inhibition, in vitro tolerance and specificity over cyclosporin A. The novel compounds might be the promising candidates for a broad-spectrum based approach to the circumvention of MDR in resistant tumors.

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Abbreviations

MDR:

Multidrug resistance

ABC:

ATP-binding cassette

Pgp:

P-glycoprotein

BCRP:

Breast cancer resistance protein

MRP:

Multidrug-resistance associated protein

LRP:

Lung resistance protein

FITC:

Fluorescein isothiocyanate

MTT:

Methylthiazolyldiphenyl-tetrazoliumbromide

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Acknowledgements

This research was supported by the Deutsche Forschungsgemeinschaft (DFG, Graduiertenkolleg 804, VJ), the Canadian Institute of Health Research Grant (MPM) and the Government of Canada Award (VJ). The authors wish to thank Jing-Hung Wang for excellent technical assistance with the transport assays and Shaun Ramdhany and the Department of Nuclear Cardiology, UHN, Toronto for providing the 99mTc-Sestamibi.

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Correspondence to Micheline Piquette-Miller.

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Jekerle, V., Klinkhammer, W., Reilly, R.M. et al. Novel tetrahydroisoquinolin-ethyl-phenylamine based multidrug resistance inhibitors with broad-spectrum modulating properties. Cancer Chemother Pharmacol 59, 61–69 (2007). https://doi.org/10.1007/s00280-006-0244-3

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