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Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 13(22 Pt 1)
- Publication Year :
- 2007
-
Abstract
- Purpose: The dose-cumulative cardiotoxicties and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance–associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes. Experimental Design: Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions. Results: Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress. Conclusion: To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance–associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.
- Subjects :
- Cancer Research
Heart Diseases
Glutathione reductase
Pharmacology
medicine.disease_cause
Lignans
Superoxide dismutase
chemistry.chemical_compound
Cyclooctanes
Mice
polycyclic compounds
medicine
Animals
Doxorubicin
Anthracyclines
Polycyclic Compounds
chemistry.chemical_classification
Cardiotoxicity
Mice, Inbred ICR
Antibiotics, Antineoplastic
biology
Chemistry
Glutathione peroxidase
Glutathione
Oncology
Enzyme inhibitor
biology.protein
Oxidation-Reduction
Oxidative stress
medicine.drug
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 13
- Issue :
- 22 Pt 1
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....5874afbded4ccde7721e679237fc089d