Daunorubicin cardiotoxicity: Evidence for the importance of the quinone moiety in a free-radical-independent mechanism

doi:10.1016/S0006-2952(00)00458-5

Biochemical Pharmacology

Volume 60, Issue 10, 15 November 2000, Pages 1435-1444

https://doi.org/10.1016/S0006-2952(00)00458-5 Get rights and content

Abstract

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98 ± 6% at 1 Hz, and 73 ± 8 and 67 ± 8% for 30 and 60 sec PRP, respectively, and 73 ± 3 and 63 ± 3% at 2 and 3 Hz, respectively, for 88 μM Daun (P < 0.05, vs pre-drug baseline values, mean ± SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force–frequency relationship or PRP contractions. Additional studies in Ca²⁺-loaded SR microsomes indicated that both Daun and 5-ID opened Ca²⁺ release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca²⁺ release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.

Section snippets

Materials and methods

Daun and all other chemicals, unless otherwise noted, were obtained from the Sigma Chemical Co. 5-ID was a gift from Farmitalia Carlo Erba. Experiments were conducted in accordance with the Declaration of Helsinki and the Guide for Care and Use of Laboratory Animals as adopted by the National Institutes of Health.

Cardiac function

Clinically useful anthracyclines such as Daun may impair cardiac contractility, at least in part, by disrupting SR function [1]. To determine whether the quinone moiety can account for the ability of Daun to both depress contractility and impair SR function, we compared the effects of Daun and 5-ID on contractility (dF/dt) of PRP contractions; the initial contractions following 20-, 30-, and 60-sec rest intervals (rested contractions) were compared with changes in dF/dt at steady state (1 Hz).

Discussion

Our results show that Daun causes selective impairment of contractility (dF/dt) of the initial contraction after a rest interval (Fig. 2A), indicating that Daun perturbs cardiac function via a mechanism that disrupts cardiac SR function. The first contraction after the rest interval is potentiated because Ca²⁺ from non-releasable SR sites moves to releasable SR sites during the rest. Thus, agents such as caffeine (Table 1) and ryanodine [20], which deplete SR Ca²⁺, inhibit rested contractions

Acknowledgements

Support for this project was provided by a Boise State University Faculty Research Grant, Mountain States Medical Research Institute, and a Department of Veterans Affairs Merit Review Grant. The authors thank Mary Hicks for her excellent technical assistance.

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Daunorubicin cardiotoxicity: Evidence for the importance of the quinone moiety in a free-radical-independent mechanism

Abstract

Section snippets

Materials and methods

Cardiac function

Discussion

Acknowledgements

J Biol Chem

J Mol Cell Cardiol

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Toxicol Appl Pharmacol

J Biol Chem

J Mol Cell Cardiol

Biochem Pharmacol

FEBS Lett

J Mol Cell Cardiol

Doxorubicin cardiotoxicityAnalysis of prevailing hypotheses

FASEB J

Anthraquinone-sensitized calcium release channel from rat cardiac sarcoplasmic reticulumPossible receptor-mediated mechanism of doxorubicin cardiomyopathy

Mol Pharmacol

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Br J Pharmacol

Patterns of interaction between anthraquinone drugs and the calcium release channel from cardiac sarcoplasmic reticulum

Circ Res