Sensitization of Cells Overexpressing Multidrug-Resistant Proteins by Pluronic P85

Elena V. Batrakova; Shu Li; Valery Yu Alakhov; William F. Elmquist; Donald W. Miller; Alexander V. Kabanov

doi:10.1023/A:1026179132599

Sensitization of Cells Overexpressing Multidrug-Resistant Proteins by Pluronic P85

Elena V. Batrakova, Shu Li, Valery Yu Alakhov, William F. Elmquist, Donald W. Miller, Alexander V. Kabanov

Pharmaceutics

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

124 Scopus citations

Abstract

Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2. Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells. Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated. Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.

Original language	English (US)
Pages (from-to)	1581-1590
Number of pages	10
Journal	Pharmaceutical research
Volume	20
Issue number	10
DOIs	https://doi.org/10.1023/A:1026179132599
State	Published - Oct 1 2003

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health grant CA89225. We would like to thank Piet Borst (Netherlands Cancer Institute, Amsterdam, Netherlands) for kindly providing MRP-transfected cell lines and Dr. Kenneth Brouwer (Glaxo Wellcome, Inc., Research Triangle Park, NC, USA) for kindly providing GF120918.

Keywords

ATP
ATPase
GSH/GST
MRP1
MRP2
Pluronic

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Sensitization of Cells Overexpressing Multidrug-Resistant Proteins by Pluronic P85",

abstract = "Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2. Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells. Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated. Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.",

keywords = "ATP, ATPase, GSH/GST, MRP1, MRP2, Pluronic",

author = "Batrakova, {Elena V.} and Shu Li and Alakhov, {Valery Yu} and Elmquist, {William F.} and Miller, {Donald W.} and Kabanov, {Alexander V.}",

note = "Funding Information: This study was supported by National Institutes of Health grant CA89225. We would like to thank Piet Borst (Netherlands Cancer Institute, Amsterdam, Netherlands) for kindly providing MRP-transfected cell lines and Dr. Kenneth Brouwer (Glaxo Wellcome, Inc., Research Triangle Park, NC, USA) for kindly providing GF120918.",

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doi = "10.1023/A:1026179132599",

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T1 - Sensitization of Cells Overexpressing Multidrug-Resistant Proteins by Pluronic P85

AU - Batrakova, Elena V.

AU - Li, Shu

AU - Alakhov, Valery Yu

AU - Elmquist, William F.

AU - Miller, Donald W.

AU - Kabanov, Alexander V.

N1 - Funding Information: This study was supported by National Institutes of Health grant CA89225. We would like to thank Piet Borst (Netherlands Cancer Institute, Amsterdam, Netherlands) for kindly providing MRP-transfected cell lines and Dr. Kenneth Brouwer (Glaxo Wellcome, Inc., Research Triangle Park, NC, USA) for kindly providing GF120918.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2. Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells. Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated. Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.

AB - Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2. Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells. Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated. Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.

KW - ATP

KW - ATPase

KW - GSH/GST

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KW - MRP2

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JO - Pharmaceutical research

JF - Pharmaceutical research

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ER -

Sensitization of Cells Overexpressing Multidrug-Resistant Proteins by Pluronic P85

Abstract

Bibliographical note

Keywords

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