MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on February 10, 2005; DOI: 10.1124/mol.104.005728

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.104.005728v1
67/5/1505    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Charlier, Jr., H. A.
Right arrow Articles by Shadle, S. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Charlier, Jr., H. A.
Right arrow Articles by Shadle, S. E.


Received for publication August 17, 2004.
Revised January 9, 2005.
Accepted for publication February 10, 2005.

Investigations of calsequestrin as a target for anthracyclines: comparison of functional effects of daunorubicin, daunorubicinol, and trifluoperazine

Henry A. Charlier, Jr. 1, Richard D. Olson 2, Carissa M. Thornock 1, Wendy K. Mercer 1, David R. Olson 2, T. Stephen Broyles 1, Dawn J. Muhlestein 1, Corianton L. Larson 1, Barry J. Cusack 2, Susan E. Shadle 1*

1 Boise State University 2 Boise Veterans Affairs Medical Center

* Address correspondence to: E-mail: sshadle{at}chem.boisestate.edu

Abstract

Anthracycline therapy is associated with a life-threatening, but poorly understood, cardiotoxicity. Effects of treatment are consistent with drug-induced disruption of cardiac sarcoplasmic reticulum (SR) calcium homeostasis, including inhibition of calcium release by anthracyclines. This effect, which depends on lumenal SR calcium concentration, is hypothesized to involve interactions of anthracyclines with the calcium binding protein, calsequestrin (CSQ). This study was designed to test the hypothesis that an interaction between CSQ and anthracyclines could be related to alterations in SR calcium release and cardiac function. The effects of the anthracycline, daunorubicin, and its metabolite, daunorubicinol, were compared to those of a known CSQ inhibitor, trifluoperazine (TFP). Protein fluorescence quenching studies demonstrated that TFP, daunorubicin, and daunorubicinol bind to CSQ with apparent binding affinities in the low micromolar range. The presence of calcium decreases the drug-dependent fluorescence quenching, probably due to calcium-induced CSQ conformational changes. TFP also inhibited SR calcium release. While the TFP IC50 value is somewhat larger than for anthracyclines, the TFP effect is also dependent on lumenal SR calcium concentration. In a muscle preparation, micromolar TFP decreased cardiac contractility in a manner that implicates the involvement of SR calcium and resembles the effects of anthracyclines. These data are consistent with a mechanism in which TFP or anthracyclines impair SR calcium release and cardiac function through a mechanism involving disruption of CSQ function. Such a mechanism may contribute to anthracycline cardiotoxicity.


Key words: Structure determinations, Structure-activity relationships and modeling, Fluorescence techniques, Protein targets


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
E. Salvatorelli, P. Menna, L. Gianni, and G. Minotti
Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies
J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 790 - 800.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Salvatorelli, S. Guarnieri, P. Menna, G. Liberi, A. M. Calafiore, M. A. Mariggio, A. Mordente, L. Gianni, and G. Minotti
Defective One- or Two-electron Reduction of the Anticancer Anthracycline Epirubicin in Human Heart: RELATIVE IMPORTANCE OF VESICULAR SEQUESTRATION AND IMPAIRED EFFICIENCY OF ELECTRON ADDITION
J. Biol. Chem., April 21, 2006; 281(16): 10990 - 11001.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
E. Kim, M. Tam, W. F. Siems, and C. Kang
Effects of Drugs with Muscle-Related Side Effects and Affinity for Calsequestrin on the Calcium Regulatory Function of Sarcoplasmic Reticulum Microsomes
Mol. Pharmacol., December 1, 2005; 68(6): 1708 - 1715.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics