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- W2003014096 abstract "The HER2-PI3K-mTOR pathway is pivotal for protecting the heart from chemotherapy drug doxorubicin (DOX). Studies from us and others have shown that the HER2 receptor and PI3Ks protect cardiomyocytes from DOX-induced apoptosis and loss of cardiac troponins. Currently, drugs targeting the HER2-PI3K-mTOR pathway are either approved or being tested in clinical trials for cancer therapy. It is, therefore, important to evaluate the cardiac effects of using these drugs alone or in combined with DOX. Three-month old female FVB/n mice were treated with BEZ235 (BEZ, a PI3K-mTOR dual inhibitor) alone or with DOX for 6-7 weeks. Cardiac function was monitored by echocardiography and hemodynamic measurements. Cardiac morphology was assessed by confocal microscopy and transmission electron microscopy. The activation of signaling molecules were measured by Western blot analysis. BEZ alone induced cardiac hypertrophy and subsequent heart failure in a course of 17 months. Combination of BEZ with DOX, either concurrently or sequentially, induced cardiac hypertrophy which was associated with a higher mortality rate compared to DOX alone. Neuregulin1(an HER receptor ligand) worsened, while Lapatinib (an HER2 inhibitor) alleviated, cardiac hypertrophy in these mice. Lapatinib increased the activation of AMPK in DOX+BEZ treated hearts. The cardiac effect of lapatinib was blocked by Compound C, an AMPK inhibitor. Metformin, an AMPK activator, alleviated DOX+BEZ induced cardiac hypertrophy. BEZ alone induced irreversible cardiac dysfunction in mice. Combined use of BEZ and DOX induced cardiac hypertrophy and early mortality, which were prevented by lapatinib. The cardioprotective effects of lapatinib may rely on activating AMPK in the heart." @default.
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- W2003014096 date "2013-08-01" @default.
- W2003014096 modified "2023-10-18" @default.
- W2003014096 title "Combined Use of a PI3K-mTOR Dual Inhibitor and Doxorubicin Induced Cardiac Hypertrophy and Early Death in Mice" @default.
- W2003014096 doi "https://doi.org/10.1016/j.cardfail.2013.06.219" @default.
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