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Mrp1 Protects Against Doxorubicin‐induced Cardiotoxicity in vitro
Author(s) -
Zhang Wei,
Coy Donna,
Deng Jun,
Vore Mary
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1179.4
Subject(s) - cardiotoxicity , doxorubicin , apoptosis , pharmacology , efflux , anthracycline , in vitro , chemistry , medicine , microbiology and biotechnology , chemotherapy , biology , cancer , biochemistry , breast cancer
Doxorubicin (DOX), an anthracycline antibiotic commonly used as a cancer chemotherapeutic agent, is well known for its ability to induce acute and chronic cardiotoxicity, leading to irreversible cardiomyopathy. In the present study, we investigated the role of multidrug resistance‐associated protein 1 (Mrp1), an ATP‐binding cassette efflux transporter, in DOX induced cardiotoxicity. We cultured cardiomyocytes (CM) and cardiac fibroblasts (CF), which were isolated from C57BL/6J (WT) or Mrp1 knock out (KO) mice (1 – 3 days old). The cells were treated with DOX (0.5 – 3 μM) and examined 24 hrs later. DOX enhanced Mrp1 mRNA (~2 fold) and protein (~2.6 fold) expression similarly in both CM and CF. The MTS assay showed that the CM from KO mice were more sensitive to DOX than WT, with an IC 50 in KO of 0.94 μM (95% CI: 0.74 – 1.18) versus 1.60 μM (95% CI: 1.20 – 2.11) in WT. Furthermore, CM and CF from KO mice showed increased caspase 3 and PARP cleavage following DOX treatment, consistent with increased apoptosis in cells from KO. These results imply that Mrp1 protects against DOX induced cardiotoxicity in cultured CM and CF. ( CA139844 )