Pharmaceutical compositions and methods for countering chemotherapy induced cardiotoxicity
Inventors
Armstrong, Christopher G. • Kim, Kevin J. • Pham, Lisa Maria Lucia • PARK, Eunhye • Zhong, Zhong • Huang, Guanyi • Wu, Joseph C. • Elmer, Sidney Paul • Visuthikraisee, Viwat • Cadag, Eithon Michael G. • Freeman, Thomas Bernard • Lum, Pek Yee
Assignees
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Publication Number
US-11786503-B2
Publication Date
2023-10-17
Expiration Date
Abstract
This disclosure provides methods and pharmaceutical compositions for reducing or eliminating cardiotoxicity, particularly cardiotoxicity induced by a cancer treatment or other therapy. In some cases, the methods and compositions prevent or reduce cardiotoxicity caused by anthracycline treatment. The methods provided herein often comprise administering a protective agent such as myricetin, tricetin, robinetin, ficetin, vitexin, quercetin, dihydrorobinetin, kaempferol, 7,3′,4′,5′-tetrahydroxyflavone, and myricitrin in conjunction with the administration of a cancer drug or other treatment. They may comprise administering a protective agent in combination with dexrazoxane. The compositions provided herein include co-formulations of a protective agent with a different protective agent or with a cancer treatment (e.g., anthracycline drug).
Core Innovation
The invention relates to pharmaceutical compositions and methods for preventing, reducing, or eliminating cardiotoxicity induced by an anticancer agent in a subject. The protective agent is administered prior to or simultaneously with the anticancer agent to provide an effective amount in the subject, and the anticancer agent is selected from protein kinase inhibitors or proteasome inhibitors, with anthracyclines also described as inducing cardiotoxicity.
The protective agent is cardioprotective flavonoids, including myricetin or a salt thereof, and related compounds such as tricetin, robinetin, ficetin, vitexin, dihydrorobinetin, 7,3′,4′,5′-tetrahydroxyflavone, and myricitrin. The document also describes co-formulations, including combinations with dexrazoxane, and substitution-parameter formulas, alongside structure-activity relationships for topoisomerase II inhibition and cardioprotection.
Structure-activity comparisons show that B-ring hydroxyl substitutions are critical for cardioprotection and TOPOIIα/β inhibition, while methoxy substitutions reduce or abolish cardioprotective potency and TOPOII inhibition and can increase cytotoxicity. The document further describes cardiotoxicity endpoints and mechanisms assessed in relation to the protective effect, including cardiac tissue damage, electrophysiological dysfunction and QT/QTc prolongation, mitochondrial toxicity, apoptosis, oxidative stress, DNA double strand break, and sarcomere disruption.
Claims Coverage
The patent contains two independent method claims. The inventive coverage centers on administering myricetin, or a salt thereof, prior to or simultaneously with an anticancer agent that is a protein kinase inhibitor or a proteasome inhibitor, to prevent, reduce, or eliminate cardiotoxicity.
Myricetin co-administration to prevent cardiotoxicity from protein kinase or proteasome inhibitors
Administering an effective amount of a protective agent prior to or simultaneously with an anticancer agent to prevent, reduce, or eliminate cardiotoxicity induced by the anticancer agent, wherein the protective agent is myricetin or a salt thereof, and wherein the anticancer agent is a protein kinase inhibitor or a proteasome inhibitor.
Cancer treatment with cardiotoxicity prevention during protein kinase or proteasome inhibitor therapy
Treating cancer in a subject by administering an effective amount of an anticancer agent and administering an effective amount of a protective agent prior to or simultaneously with the anticancer agent, wherein the protective agent is myricetin or a salt thereof, wherein the anticancer agent is a protein kinase inhibitor or a proteasome inhibitor, and wherein the administration prevents, reduces, or eliminates cardiotoxicity induced by the anticancer agent in the subject.
Across the two independent claims, the core claim coverage is directed to cardiotoxicity prevention by administering myricetin, or a salt thereof, before or at the same time as an anticancer agent that is a protein kinase inhibitor or a proteasome inhibitor.
Stated Advantages
Prevents, reduces, or eliminates cardiotoxicity induced by the anticancer agent.
Provides cardioprotection and preserves cardiac function.
Reduces the risk of cardiotoxicity.
Documented Applications
Preventing, reducing, or eliminating cardiotoxicity induced by an anticancer agent in a subject, including cardiotoxicity associated with protein kinase inhibitors and proteasome inhibitors.
Treating cancer in a subject while preventing, reducing, or eliminating cardiotoxicity induced by an anticancer agent.
Protecting cardiomyocytes, including iPSC-derived cardiomyocytes, against cardiotoxicity induced by anticancer agents such as anthracyclines and other cardiotoxic agents including protein kinase inhibitors and a proteasome inhibitor, with additional described testing including lack of interference with doxorubicin anti-cancer activity in breast cancer cells.
In vivo doxorubicin cardioprotection via improved echocardiographic fractional shortening/ejection fraction in mice.
In vitro protection results are also described for other protectants including vitexin.
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