TY - JOUR
T1 - Antithetical actions of mitoxantrone and doxorubicin on ryanodine- sensitive Ca++ release channels of rat cardiac sarcoplasmic reticulum
T2 - Evidence for a competitive mechanism
AU - Kim, E.
AU - Giri, S. N.
AU - Pessah, Isaac N
PY - 1994
Y1 - 1994
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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M3 - Article
C2 - 8138934
AN - SCOPUS:0028202790
VL - 268
SP - 1212
EP - 1221
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -