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) 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 (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 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:The use of anthracycline antibiotics such as doxorubicin (DOX) has greatly improved the mortality and morbidity of cancer patients. However, the associated risk of cardiomyopathy has limited their clinical application. DOX-associated cardiotoxicity is irreversible and progresses to heart failure (HF). For this reason, a better understanding of the molecular mechanisms underlying these adverse cardiac effects is essential to develop improved regimes that include cardioprotective strategies. MicroRNAs (miRNAs) are short non-coding RNAs that are able to post-trascriptionally regulate gene expression. MiRNAs have been demonstrated to be involved in both cancer and cardiovascular disease. Therefore, we were interested in unveiling the potential role of miRNAs in chemotherapy-induced HF. We used a combination of three different models to recreate this cardiac toxicity (acute in vitro DOX treatment, DOX-induced HF in vivo and a myocardial infarction -MI- leading to failure model) to study the pattern of dysregulated miRNAs. Using RNA from all three conditions, miRNA microarray profiling was performed and a common miRNA signature was identified. Interestingly, these dysregulated miRNAs have been previously identified as involved in the failing heart. Our results suggest that DOX is able to alter the expression of miRNAs implicated in HF, in vitro as well as in vivo. The present study is a microRNA profiling of the damaged cardiac muscle (cardiomyocyte cell population), following either myocardial infarction (MI) induction or doxorubicin (DOX) treatment. Two DOX-treated models were included: ARC exposed to DOX in vitro and a validated DOX-induced heart failure model generated by repeated administration of DOX injections.
