Davallialactone protects against adriamycin-induced cardiotoxicity in vitro and in vivo

Department of Pediatrics, Chonbuk National University Hospital, 634-18 Keumam-dong, Jeonju 561-712, Republic of Korea.
Journal of Natural Medicines (Impact Factor: 1.59). 08/2011; 66(1):149-57. DOI: 10.1007/s11418-011-0567-1
Source: PubMed


Adriamycin (ADR) is a potent anticancer drug. Its clinical applications are limited due to its cardiotoxicity. Oxidative stress is responsible for cardiomyopathy induced by ADR. Previous studies have demonstrated that davallialactone (DAVA), extracted from mushroom Inonotus xeranticus, has potential antiplatelet aggregation activity and free radical scavenging properties. In this study, we investigated whether DAVA has protective effects against ADR-induced free radical accumulation and apoptosis in cardiac muscle cells and compared the effects of DAVA with N-acetylcysteine, a potent antioxidant. We evaluated the effect of DAVA on ADR-induced cytotoxicity by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and crystal violet staining, the reactive oxygen species (ROS) production by flow cytometry, and the expression of stress-related proteins like Cu/Zn superoxide dismutase (SOD), Mn-SOD, and the involvement of mitogen-activated protein kinase pathway by Western blot analysis. Apoptosis was assessed by nuclear condensation and the expression levels of pro-apoptotic proteins, such as caspase-3 and polyadenosine diphosphate-ribose polymerase (PARP). The cardio-protective effects of DAVA were also evaluated in an in vivo study in an animal model of ADR-induced acute cardiomyopathy. Our results showed that DAVA significantly increased the viability of doxorubicin-injured H9c2 cells and inhibited ADR-induced ROS production, apoptosis, and the expression of Cu/Zn SOD and Mn-SOD. DAVA also inhibited the expression of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which was activated by ADR. In the in vivo animal model, treatment involving DAVA significantly reduced cardiomyocyte lesions. These results suggest that DAVA is a potentially protective agent for ADR-induced cardiotoxicity in cardiomyocytes and can be a potential candidate to protect against cardiotoxicity in ADR-treated cancer patients.

Download full-text


Available from: Sankarganesh Arunachalam,
29 Reads
  • Source
    • "To overcome the cardiotoxic effect of anthracyclines the use of antioxidants have been suggested [38, 39], however antioxidants has proven to be useful in delaying or preventing chronic cardiotoxicity in rodents [40] but not in dogs [41] or sheep [42]. For patients, contradictory results have been reported showing positive [43, 44] or no [45] effect. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiotoxicity is an important side effect of cytotoxic drugs and may be a risk factor of long-term morbidity for both patients during therapy and also for staff exposed during the phases of manipulation of antiblastic drugs. The mechanism of cardiotoxicity studied in vitro and in vivo essentially concerns the formation of free radicals leading to oxidative stress, with apoptosis of cardiac cells or immunologic reactions, but other mechanisms may play a role in antiblastic-induced cardiotoxicity. Actually, some new cytotoxic drugs like trastuzumab and cyclopentenyl cytosine show cardiotoxic effects. In this report we discuss the different mechanisms of cardiotoxicity induced by antiblastic drugs assessed using animal models.
    BioMed Research International 02/2014; 2014:240642. DOI:10.1155/2014/240642 · 2.71 Impact Factor
  • Source
    • "In this study, Rh2 was demonstrated with the comparable protective activity, which was also similar to several published anti-oxidants, such as schisandrin B, davallialacton, and probucol. These compounds mentioned above were all reported to exert their cardioprotective activities through detoxification of free radicals [4] [6] [10], which contributed to the occurrence of DOX-induced pathology changes [1]. All of these evidences indicated the protective effect of Rh2 in H9C2 cell might contribute to its direct anti-oxidant property. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity. In vitro study on H9C2 cell line, as well as in vivo investigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.
    Evidence-based Complementary and Alternative Medicine 10/2012; 2012:506214. DOI:10.1155/2012/506214 · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study the protective effects of davallialactone (1), isolated from Inonotus xeranticus, have been examined against carbon tetrachloride (CCl(4))-induced acute liver injury. Mice received subcutaneous injection of 1 (2.5, 5, and 10 mg/kg) for three days before CCl(4) injection (1 mg/kg). Protection from liver injury by 1 was confirmed by the observation of decreased serum transaminases and diminished necrosis of liver tissue. Reduced hepatic injury was very similar to that observed with silymarin, a known hepatoprotective drug used in this work for comparison. The groups treated with 1 had reduced reactive oxygen species (ROS), reduced serum malonyldialdehyde levels, and increased levels of liver Cu/Zn superoxide dismutase, as compared to the CCl(4) control group. The expression of heme oxygenase-1 in the liver tissue was increased and the activity of liver cytochrome P4502E1 was restored in the mice treated with 1. In addition, levels of serum tumor necrosis factor-alpha (TNF-α), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), numbers of macrophage, and cleaved caspase-3-positive hepatocytes were reduced in the groups treated with 1. These findings suggest that davallialactone has protective effects against CCl(4)-induced acute liver injury, and this protection is likely due to the suppression of ROS-induced lipid peroxidation and inflammatory response.
    Journal of Natural Products 10/2012; 75(10). DOI:10.1021/np300099a · 3.80 Impact Factor
Show more