Role of copper transporters in resistance to platinating agents

Cara Rabik, Edward B. Maryon, Kristen Kasza, John T. Shafer, Catherine M. Bartnik, M. Eileen Dolan

Research output: Contribution to journalArticle

Abstract

Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O 6-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O 6-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O 6-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume64
Issue number1
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Fingerprint

Cisplatin
Copper
oxaliplatin
Cytotoxicity
Carboplatin
Cells
HEK293 Cells
Fibroblasts
Platinum
Pharmaceutical Preparations
Modulators
Cell Line
O(6)-benzylguanine

Keywords

  • ATP7A
  • ATP7B
  • Carboplatin
  • Cisplatin
  • HCtr1
  • O -Benzylguanine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Rabik, C., Maryon, E. B., Kasza, K., Shafer, J. T., Bartnik, C. M., & Dolan, M. E. (2009). Role of copper transporters in resistance to platinating agents. Cancer Chemotherapy and Pharmacology, 64(1), 133-142. https://doi.org/10.1007/s00280-008-0860-1

Role of copper transporters in resistance to platinating agents. / Rabik, Cara; Maryon, Edward B.; Kasza, Kristen; Shafer, John T.; Bartnik, Catherine M.; Dolan, M. Eileen.

In: Cancer Chemotherapy and Pharmacology, Vol. 64, No. 1, 01.06.2009, p. 133-142.

Research output: Contribution to journalArticle

Rabik, C, Maryon, EB, Kasza, K, Shafer, JT, Bartnik, CM & Dolan, ME 2009, 'Role of copper transporters in resistance to platinating agents', Cancer Chemotherapy and Pharmacology, vol. 64, no. 1, pp. 133-142. https://doi.org/10.1007/s00280-008-0860-1
Rabik, Cara ; Maryon, Edward B. ; Kasza, Kristen ; Shafer, John T. ; Bartnik, Catherine M. ; Dolan, M. Eileen. / Role of copper transporters in resistance to platinating agents. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 64, No. 1. pp. 133-142.
@article{35aca8a14eb84b49a6b0888332c640b2,
title = "Role of copper transporters in resistance to platinating agents",
abstract = "Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O 6-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O 6-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O 6-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.",
keywords = "ATP7A, ATP7B, Carboplatin, Cisplatin, HCtr1, O -Benzylguanine",
author = "Cara Rabik and Maryon, {Edward B.} and Kristen Kasza and Shafer, {John T.} and Bartnik, {Catherine M.} and Dolan, {M. Eileen}",
year = "2009",
month = "6",
day = "1",
doi = "10.1007/s00280-008-0860-1",
language = "English (US)",
volume = "64",
pages = "133--142",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Role of copper transporters in resistance to platinating agents

AU - Rabik, Cara

AU - Maryon, Edward B.

AU - Kasza, Kristen

AU - Shafer, John T.

AU - Bartnik, Catherine M.

AU - Dolan, M. Eileen

PY - 2009/6/1

Y1 - 2009/6/1

N2 - Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O 6-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O 6-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O 6-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.

AB - Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O 6-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O 6-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O 6-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.

KW - ATP7A

KW - ATP7B

KW - Carboplatin

KW - Cisplatin

KW - HCtr1

KW - O -Benzylguanine

UR - http://www.scopus.com/inward/record.url?scp=67349215472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67349215472&partnerID=8YFLogxK

U2 - 10.1007/s00280-008-0860-1

DO - 10.1007/s00280-008-0860-1

M3 - Article

C2 - 18998134

AN - SCOPUS:67349215472

VL - 64

SP - 133

EP - 142

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -