Background: Doxorubicin (Dox) is one of the most effective chemotherapy agents used in the treatment of solid tumors and hematological malignancies. However, it causes dose-related cardiotoxicity that may lead to heart failure in patients. Luteolin (Lut) is a common flavonoid that exists in many types of plants. It has been studied for treating various diseases such as hypertension, inflammatory disorders, and cancer. In this study, we evaluated the cardioprotective and anticancer effects of Lut on Dox-induced cardiomyopathy in vitro and in vivo to explore related mechanisms in alleviating dynamin-related protein (Drp1)-mediated mitochondrial apoptosis.Methods: MTT and LDH assay were used to determine the viability and toxicity of cardiomyocytes treated with Dox and Lut. Flow cytometry was used to examine ROS levels, and electron and confocal microscopy was employed to assess the mitochondrial morphology. The level of apoptosis was examined by Hoechst 33258 staining. The protein levels of myocardial fission protein and apoptosis-related protein were examined using Western blot. Transcriptome analysis of the protective effect of Lut against Dox-induced cardiac toxicity in myocardial cells was performed using RNA sequencing technology. The protective effects of Lut against cardiotoxicity mediated by Dox in zebrafish were quantified. The effect of Lut increase the antitumor activity of Dox in breast cancer both in vitro and in vivo were further employed.Results: Lut ameliorated Dox-induced toxicity in H9c2 and AC16 cells. The level of oxidative stress was downregulated by Lut after Dox treatment of myocardial cells. Lut effectively reduced the increased mitochondrial fission post Dox stimulation in cardiomyocytes. Apoptosis, fission protein Drp1, and Ser616 phosphorylation were also increased post Dox and reduced by Lut. In the zebrafish model, Lut significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, in the mouse model, Lut prevented Dox-induced cardiotoxicity and enhanced the cytotoxicity in triple-negative breast cancer by inhibiting proliferation and metastasis and inducing apoptosis.

Osthole inhibits bone metastasis of breast cancer

Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant setting. Unfortunately, anthracycline-associated dose-dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little effect in clinical trials. Herbal medicines are pure, natural substances that have been used for centuries in many countries, including China. This trial aims to evaluate the cardioprotective effects and safety of Platycodon grandiflorum granules compared to placebo granules in patients with early breast cancer receiving anthracycline-based chemotherapy. This study is a single-center, double-blinded, randomized, placebo-controlled, parallel-group trial. A total of 120 patients will be randomly allocated in a 1:1 ratio to receive either P. grandiflorum granules or placebo granules twice daily for 12 weeks. The primary outcome is heart failure (either clinical or subclinical). The secondary outcomes include all-cause mortality, cardiac death, electrocardiogram (ECG) findings, left ventricular diastolic function, longitudinal systolic strain and velocities measured by tissue Doppler imaging, cardiac biomarkers, such as troponin I (TnI), brain natriuretic peptide (BNP), and creatine kinase isoenzymes (CK-MB). Assessments will be performed at baseline (before randomization) and 3, 6, 9, 12, 16, and 20 weeks after randomization. This will be the first clinical trial to evaluate the cardioprotective effects and safety of P. grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy. We are also performing this trial to assess the feasibility of a larger-scale clinical trial in the future. Chinese Clinical Trial Registry, ChiCTR-IPR-16009256 . Registered on 23 September 2016.

Background: Xian-ling-lian-xia-fang (XLLXF), a Chinese medicine decoction, is widely used in the treatment of triple negative breast cancer (TNBC). However, the underlying mechanism of XLLXF in TNBC treatment has not been totally elucidated. Methods: Here, network pharmacology and molecular docking were used to explore the mechanism of Traditional Chinese medicine in the treatment of TNBC. Then, biological experiments were integrated to verify the results of network pharmacology. Results: Network pharmacology showed that the candidate active ingredients mainly included quercetin, kaempferol, stigmasterol, and β-sitosterol through the “XLLXF–active ingredients–targets” network. Vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase (MMP) 2 were the potential therapeutic targets obtained through the protein–protein interaction (PPI) network. Molecular docking confirmed that quercetin, kaempferol, stigmasterol, and β-sitosterol could stably combine with VEGFA and MMP2. Experimental verification showed that XLLXF could inhibit proliferation, colony ability, and vasculogenic mimicry (VM) formation and promote cell apoptosis in TNBC. Laser confocal microscopy found that XLLXF impaired F-actin cytoskeleton organization and inhibited epithelial mesenchymal transition. Animal experiments also found that XLLXF could inhibit tumor growth and VM formation in TNBC xenograft model. Western blot analysis and immunohistochemical staining showed that XLLXF inhibited the protein expression of VEGFA, MMP2, MMP9, Vimentin, VE-cadherin, and Twist1 and increased that of E-cadherin, tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-3 in vitro and in vivo. Conclusions: Integrating the analysis of network pharmacology and experimental validation revealed that XLLXF could inhibit VM formation via downregulating the VEGF/MMPs signaling pathway.