Antithetical actions of mitoxantrone and doxorubicin on ryanodine- sensitive Ca++ release channels of rat cardiac sarcoplasmic reticulum: Evidence for a competitive mechanism

E. Kim, S. N. Giri, Isaac N Pessah

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Abstract

The anthracenedione mitoxantrone (MTX) is examined for activity toward ryanodine-sensitive Ca++ release channels (i.e., ryanodine receptors; RyR) from rat cardiac SR singly or in combination with doxorubicin (DXR). MTX and DXR exhibit antithetical activities toward RyR. Under conditions promoting channel closure, DXR enhances the binding of [3H]ryanodine (EC50 = 44 μM), whereas MTX has higher affinity (EC50 = 25 μM) but > 10-fold lower activity towards activating RyR. Unlike DXR, MTX assayed under conditions promoting channel activation inhibits the binding of [3H]ryanodine (IC50 = 3.3 μM) and does not alter the potency with which Ca++ activates RyR in the presence or absence of Mg++. In the presence of Mg++, MTX does not alter k(obs) and slows k-1 for [3H]ryanodine binding, whereas DXR accelerates k(obs) with little change in k-1. The antithetical behavior of MTX and DXR at the RyR raises the possibility that MTX antagonizes the ability of DXR to activate the RyR when the drugs are present in combination. In consonance with this hypothesis, MTX inhibits DXR (60 μM)-sensitized [3H]ryanodine-binding sites in a dose-dependent manner (IC50 = 8.4 μM) and shifts the EC50 for DXR-activated [3H]ryanodine-binding without reducing the maximum occupancy attained at high DXR concentration, revealing the competitive nature of the interaction of DXR and MTX. MTX singly does not alter active Ca++ accumulation by SR but is shown to fully inhibit DXR- induced Ca++ release. The results suggest that MTX antagonizes DXR- activated RyR by binding to mutually exclusive sites and may provide a rational basis for combination therapy aimed at extending the current dose limits of DXR.

Original languageEnglish (US)
Pages (from-to)1212-1221
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume268
Issue number3
StatePublished - 1994

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Ryanodine
Mitoxantrone
Sarcoplasmic Reticulum
Doxorubicin
Inhibitory Concentration 50
Anthraquinones
Ryanodine Receptor Calcium Release Channel
Aptitude

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Antithetical actions of mitoxantrone and doxorubicin on ryanodine- sensitive Ca++ release channels of rat cardiac sarcoplasmic reticulum: Evidence for a competitive mechanism",
abstract = "The anthracenedione mitoxantrone (MTX) is examined for activity toward ryanodine-sensitive Ca++ release channels (i.e., ryanodine receptors; RyR) from rat cardiac SR singly or in combination with doxorubicin (DXR). MTX and DXR exhibit antithetical activities toward RyR. Under conditions promoting channel closure, DXR enhances the binding of [3H]ryanodine (EC50 = 44 μM), whereas MTX has higher affinity (EC50 = 25 μM) but > 10-fold lower activity towards activating RyR. Unlike DXR, MTX assayed under conditions promoting channel activation inhibits the binding of [3H]ryanodine (IC50 = 3.3 μM) and does not alter the potency with which Ca++ activates RyR in the presence or absence of Mg++. In the presence of Mg++, MTX does not alter k(obs) and slows k-1 for [3H]ryanodine binding, whereas DXR accelerates k(obs) with little change in k-1. The antithetical behavior of MTX and DXR at the RyR raises the possibility that MTX antagonizes the ability of DXR to activate the RyR when the drugs are present in combination. In consonance with this hypothesis, MTX inhibits DXR (60 μM)-sensitized [3H]ryanodine-binding sites in a dose-dependent manner (IC50 = 8.4 μM) and shifts the EC50 for DXR-activated [3H]ryanodine-binding without reducing the maximum occupancy attained at high DXR concentration, revealing the competitive nature of the interaction of DXR and MTX. MTX singly does not alter active Ca++ accumulation by SR but is shown to fully inhibit DXR- induced Ca++ release. The results suggest that MTX antagonizes DXR- activated RyR by binding to mutually exclusive sites and may provide a rational basis for combination therapy aimed at extending the current dose limits of DXR.",
author = "E. Kim and Giri, {S. N.} and Pessah, {Isaac N}",
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T1 - Antithetical actions of mitoxantrone and doxorubicin on ryanodine- sensitive Ca++ release channels of rat cardiac sarcoplasmic reticulum

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AU - Giri, S. N.

AU - Pessah, Isaac N

PY - 1994

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N2 - The anthracenedione mitoxantrone (MTX) is examined for activity toward ryanodine-sensitive Ca++ release channels (i.e., ryanodine receptors; RyR) from rat cardiac SR singly or in combination with doxorubicin (DXR). MTX and DXR exhibit antithetical activities toward RyR. Under conditions promoting channel closure, DXR enhances the binding of [3H]ryanodine (EC50 = 44 μM), whereas MTX has higher affinity (EC50 = 25 μM) but > 10-fold lower activity towards activating RyR. Unlike DXR, MTX assayed under conditions promoting channel activation inhibits the binding of [3H]ryanodine (IC50 = 3.3 μM) and does not alter the potency with which Ca++ activates RyR in the presence or absence of Mg++. In the presence of Mg++, MTX does not alter k(obs) and slows k-1 for [3H]ryanodine binding, whereas DXR accelerates k(obs) with little change in k-1. The antithetical behavior of MTX and DXR at the RyR raises the possibility that MTX antagonizes the ability of DXR to activate the RyR when the drugs are present in combination. In consonance with this hypothesis, MTX inhibits DXR (60 μM)-sensitized [3H]ryanodine-binding sites in a dose-dependent manner (IC50 = 8.4 μM) and shifts the EC50 for DXR-activated [3H]ryanodine-binding without reducing the maximum occupancy attained at high DXR concentration, revealing the competitive nature of the interaction of DXR and MTX. MTX singly does not alter active Ca++ accumulation by SR but is shown to fully inhibit DXR- induced Ca++ release. The results suggest that MTX antagonizes DXR- activated RyR by binding to mutually exclusive sites and may provide a rational basis for combination therapy aimed at extending the current dose limits of DXR.

AB - The anthracenedione mitoxantrone (MTX) is examined for activity toward ryanodine-sensitive Ca++ release channels (i.e., ryanodine receptors; RyR) from rat cardiac SR singly or in combination with doxorubicin (DXR). MTX and DXR exhibit antithetical activities toward RyR. Under conditions promoting channel closure, DXR enhances the binding of [3H]ryanodine (EC50 = 44 μM), whereas MTX has higher affinity (EC50 = 25 μM) but > 10-fold lower activity towards activating RyR. Unlike DXR, MTX assayed under conditions promoting channel activation inhibits the binding of [3H]ryanodine (IC50 = 3.3 μM) and does not alter the potency with which Ca++ activates RyR in the presence or absence of Mg++. In the presence of Mg++, MTX does not alter k(obs) and slows k-1 for [3H]ryanodine binding, whereas DXR accelerates k(obs) with little change in k-1. The antithetical behavior of MTX and DXR at the RyR raises the possibility that MTX antagonizes the ability of DXR to activate the RyR when the drugs are present in combination. In consonance with this hypothesis, MTX inhibits DXR (60 μM)-sensitized [3H]ryanodine-binding sites in a dose-dependent manner (IC50 = 8.4 μM) and shifts the EC50 for DXR-activated [3H]ryanodine-binding without reducing the maximum occupancy attained at high DXR concentration, revealing the competitive nature of the interaction of DXR and MTX. MTX singly does not alter active Ca++ accumulation by SR but is shown to fully inhibit DXR- induced Ca++ release. The results suggest that MTX antagonizes DXR- activated RyR by binding to mutually exclusive sites and may provide a rational basis for combination therapy aimed at extending the current dose limits of DXR.

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