Inhibition of buthionine sulfoximine-enhanced doxorubicin toxicity in metallothionein overexpressing transgenic mouse heart

Hui Yun Wu, Yujian Kang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60% in both transgenic and non-transgenic mice. DOX- induced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)515-520
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume287
Issue number2
StatePublished - Dec 1 1998
Externally publishedYes

Fingerprint

Buthionine Sulfoximine
Metallothionein
Doxorubicin
Transgenic Mice
Drug Resistance
Neoplasms
Creatine Kinase
Malondialdehyde
Glutathione
Injections
Cardiotoxicity

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

@article{8e2a752e4a364bb08a0e7f1374a4cfd2,
title = "Inhibition of buthionine sulfoximine-enhanced doxorubicin toxicity in metallothionein overexpressing transgenic mouse heart",
abstract = "Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60{\%} in both transgenic and non-transgenic mice. DOX- induced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.",
author = "Wu, {Hui Yun} and Yujian Kang",
year = "1998",
month = "12",
day = "1",
language = "English (US)",
volume = "287",
pages = "515--520",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Inhibition of buthionine sulfoximine-enhanced doxorubicin toxicity in metallothionein overexpressing transgenic mouse heart

AU - Wu, Hui Yun

AU - Kang, Yujian

PY - 1998/12/1

Y1 - 1998/12/1

N2 - Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60% in both transgenic and non-transgenic mice. DOX- induced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.

AB - Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60% in both transgenic and non-transgenic mice. DOX- induced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.

UR - http://www.scopus.com/inward/record.url?scp=0032463529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032463529&partnerID=8YFLogxK

M3 - Article

VL - 287

SP - 515

EP - 520

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -