Reduced cyclosporin accumulation in multidrug-resistant cells

Howard Goldberg; Victor Ling; Pui Y. Wong; Karl Skorecki

doi:10.1016/s0006-291x(88)80073-1

Reduced cyclosporin accumulation in multidrug-resistant cells

Howard Goldberg, Victor Ling, Pui Y. Wong, Karl Skorecki

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

Cyclosporin accumulation was reduced by 50 % or more in multidrug- resistant CH^RC5 CHO cells with high levels of P-glycoprotein expression compared to drug sensitive AuxB1 CHO cells. This difference could be overcome by verapamil which is known to interact with P-glycoprotein and reverse multidrug resistance. The difference in cyclosporin accumulation between sensitive and resistant cells decreased with increasing cyclosporin concentrations suggesting that cyclosporine itself regulated its own accumulation through interaction with P-glycoprotein. Indeed, cyclosporin also reversed differences in vinblastine accumulation between resistant and sensitive cells lines. Since P-glycoprotein is highly expressed in the kidney which is also a target for cyclosporin toxicity, the effects of verapamil on cyclosporin accumulation were studied in two renal cell lines, rat mesangial cells and LLCPK₁, cells. Verapamil increased cyclosporin accumulation by approximately 70 %. These results suggest that cellular cyclosporine accumulation is regulated at least in part by its interaction with P-glycoprotein.

Original language	English
Pages (from-to)	552-558
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	152
Issue number	2
DOIs	https://doi.org/10.1016/s0006-291x(88)80073-1
State	Published - 29 Apr 1988
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements This research was supported by grants from Sandoz, Canada and the Medical Research Council of Canada.(KS), National Cancer Institute of Canada(VL) and the National Institutes of Health, USA (VL). Howard Goldberg is a fellow of the Kidney Foundation of Canada. We wish to thank Paula Clayman for her excellent technical assistance.

Funding

Acknowledgements This research was supported by grants from Sandoz, Canada and the Medical Research Council of Canada.(KS), National Cancer Institute of Canada(VL) and the National Institutes of Health, USA (VL). Howard Goldberg is a fellow of the Kidney Foundation of Canada. We wish to thank Paula Clayman for her excellent technical assistance.

Funders	Funder number
National Cancer Institute of Canada
Sandoz, Canada
VL
National Institutes of Health
Medical Research Council Canada

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abstract = "Cyclosporin accumulation was reduced by 50 % or more in multidrug- resistant CHRC5 CHO cells with high levels of P-glycoprotein expression compared to drug sensitive AuxB1 CHO cells. This difference could be overcome by verapamil which is known to interact with P-glycoprotein and reverse multidrug resistance. The difference in cyclosporin accumulation between sensitive and resistant cells decreased with increasing cyclosporin concentrations suggesting that cyclosporine itself regulated its own accumulation through interaction with P-glycoprotein. Indeed, cyclosporin also reversed differences in vinblastine accumulation between resistant and sensitive cells lines. Since P-glycoprotein is highly expressed in the kidney which is also a target for cyclosporin toxicity, the effects of verapamil on cyclosporin accumulation were studied in two renal cell lines, rat mesangial cells and LLCPK1, cells. Verapamil increased cyclosporin accumulation by approximately 70 %. These results suggest that cellular cyclosporine accumulation is regulated at least in part by its interaction with P-glycoprotein.",

author = "Howard Goldberg and Victor Ling and Wong, {Pui Y.} and Karl Skorecki",

note = "Funding Information: Acknowledgements This research was supported by grants from Sandoz, Canada and the Medical Research Council of Canada.(KS), National Cancer Institute of Canada(VL) and the National Institutes of Health, USA (VL). Howard Goldberg is a fellow of the Kidney Foundation of Canada. We wish to thank Paula Clayman for her excellent technical assistance.",

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Reduced cyclosporin accumulation in multidrug-resistant cells

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