Project description:Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies only offer modest protection. Using stem cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified OCT3 (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in mice revealed that targeting OCT3 can attenuate cardiac dysfunction without compromising the anticancer properties of doxorubicin. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity
Project description:Doxorubicin (DOX) has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell dysfunction is recoginized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. Endothelial TFEB protects against EC damage and cardiac dysfunction. Cardiac single cells isolated from vehicle and doxorubicin treated wild type and EC-Tfeb Tg mice were collected for scRNA-seq analysis.
Project description:Doxorubicin (DOX) is an effective anthracycline agent used to combat many neoplastic diseases. However, DOX causes cardiovascular toxicity in juvenile and young adult cancer survivors that can lead to future cardiomyopathy. Thus, it is essential to address the cardiovascular toxicity caused by DOX to improve the long-term health of cancer patients. Several studies have suggested that soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) are implicated in cardiovascular diseases by impairing vascular health and promoting the transition of Endothelial cells to Mesenchymal cells (EndMT). Given the role of sEH and COX-2 in EndMT cardiovascular toxicity, we aimed to investigate the effect of a dual sEH/COX-2 inhibitor, PTUPB, on DOX-induced EndMT, vascular and cardiac toxicity. We tested the beneficial effect of PTUPB on DOX-induced cardiovascular toxicity in zebrafish.
Project description:Doxorubicin induces cardiomypathy in oncology patients. This study is aimed at identifying molecular mechanisms of doxorubicin cardiac toxicity in rats. Transcription profiling of heart tissue of rats treated with saline or doxorubicin 1, 2 or 3 mg/kg/week by iv once per week for 2, 4 or 6 weeks. Some animals were allowed to recovery from drug administration for 2 or 4 weeks. Note the recovery column refers to whether an animal was let without drug for some weeks before sacrifice.
Project description:We used 3-dimensional proteomic profiling to discover new biomarkers associated with doxorubicin and trastuzumab-induced cardiac dysfunction.
Project description:Doxorubicin (DOX) is a potent anti-cancer drug that could induce cardiotoxicity in human bodies. To elucidate the underlying mechanisms behind DOX-induced toxicity, we conducted RNA sequencing on AC16, a well-established immortalized cardiac cell line, after treating it with DOX for 2, 4, and 6 days. We then performed RNA-Seq analysis on the obtained data. Our findings reveal significant alterations in key pathways within the AC16 cells treated with DOX, including disruptions in the MAPK cascade, apoptosis, inflammation, immune response, angiogenesis, and cardiac hypertrophy.
Project description:Doxorubicin-induced cardiomyopathy (DiCM) is a leading cause of heart failure and mortality in cancer patients, with doxorubicin-induced cardiomyocyte apoptosis constituting a fundamental pathological mechanism. Cardiac resident macrophages are primarily responsible for the effective clearance of apoptotic cardiomyocytes (efferocytosis), a process pivotal for suppressing inflammatory response and adverse cardiac remodeling. To identify genes implicated in DiCM, RNA sequencing was performed using heart tissues from saline- and DOX-treated wild-type (WT) mice. Ubiquitin mass spectrometry was used to identify the ubiquitin site of nuclear receptor subfamily 1 group H member 2 (NR1H2).
