pirarubicin and Cardiotoxicity

Pirarubicin (THP) is one of the classic chemotherapy drugs for cancer treatment. It is often clinically limited because of its cardiotoxicity. The occurrence and development of THP-mediated chemotherapy-related cardiotoxicity (CRC) may be reversed by RING finger protein 10 (RNF10). This study was performed with the aim of evaluating the inhibitory effect of RNF10 on THP-mediated CRC and its molecular mechanism. In vivo, we found that the expression of RNF10 decreased in THP-induced CRC rats, accompanied by Meox2 inhibition and AP-1 activation, resulting in increased cardiomyocyte apoptosis. After small interfering RNA (siRNA) and lentivirus transfection (Lv) of RNF10 in vitro, the expression of RNF10, Meox2, and AP-1 proteins and the degree of cardiomyocyte apoptosis were detected. We found that overexpression of RNF10 in H9C2 cardiomyocytes significantly promoted Meox2 and inhibited AP-1, alleviated apoptosis, and showed further inhibitory activity on THP-induced cardiomyocyte toxicity. Silencing RNF10 showed the opposite result. Our study showed that RNF10 inhibited THP-induced CRC through the activity of Meox2 and AP-1 proteins. RNF10 may be the next drug target for the treatment of CRC and other related cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiotoxicity; Carrier Proteins; Myocytes, Cardiac; Nerve Tissue Proteins; Rats; RNA, Small Interfering; Transcription Factor AP-1

Pirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP.. A cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1β were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots.. THP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP.. Our study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

Topics: Animals; Arrhythmias, Cardiac; Cardiotoxicity; Carrier Proteins; Inflammation; Interleukin-6; Nerve Tissue Proteins; NF-kappa B; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Pirarubicin (THP) is a widely used antitumor drug in clinical practice, but its cardiotoxicity limits its use. There is an urgent need to find drugs to alleviate the cardiotoxicity of THP. This study aimed to investigate the effect and mechanism of miR-494-3p on THP-induced cardiomyocytes.. THP induced immortalized mouse cardiomyocytes HL-1, silenced or overexpressed miR-494-3p. The effects of miR-494-3p on HL-1 contained in THP were investigated by CCK8, flow cytometry, ROS detection, JC-1 mitochondrial membrane potential detection, TUNEL cell apoptosis detection, RT-qPCR, and Western blot.. miR-494-3p could reduce cell viability, increase oxidative damage, and promote cell apoptosis; at the same time, it inhibited the expression of MDM4, promoted the activation of p53, and promoted the expression of apoptosis-related proteins. MiR-494-3p inhibitors have the opposite effect.. miR-494-3p can aggravate THP damage to HL-1, which may be achieved by downregulating MDM4 and promoting p53. miR-494-3p is one of the important miRNAs in THP-induced cardiotoxicity, which provides theoretical support for its possible use as a therapeutic target for THP-induced cardiovascular disease.

Topics: Animals; Apoptosis; Cardiotoxicity; Mice; MicroRNAs; Myocytes, Cardiac; Signal Transduction; Tumor Suppressor Protein p53

Topics: Animals; Apoptosis; Cardiotoxicity; Doxorubicin; Mice; MicroRNAs; RNA, Long Noncoding

Chinese herbal medicine is widely used because it has a good safety profile and few side effects. However, the risk of adverse drug reactions caused by herb-drug interactions (HDIs) is often overlooked. Therefore, the task of identifying possible HDIs and elucidating their mechanisms is of great significance for the prevention and treatment of HDI-related adverse reactions. Since extract from Dioscorea bulbifera L. rhizomes (DB) can cause various degrees of liver damage, it is speculated that HDIs may occur between DB extract and chemicals metabolized or excreted by the liver. Our study revealed that the cardiotoxicity of pirarubicin (THP) was increased by co-administration of DB, and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in the liver was inhibited by DB extract, which led to the accumulation of THP in heart tissue. In conclusion, there are risks of the co-administration of DB extract and THP. The mechanism of HDIs can be better revealed by targeting the efflux transporters.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers; Cardiotonic Agents; Cardiotoxicity; Chromatography, High Pressure Liquid; Dioscorea; Doxorubicin; Gene Expression Regulation; Immunohistochemistry; Liver; Male; Mice; Molecular Structure; Multidrug Resistance-Associated Protein 2; Plant Extracts; Rhizome

Pirarubicin (THP), one of the anthracycline anticancer drugs, is widely used in the treatment of various types of cancer, but its cardiotoxicity cannot be ignored. Canagliflozin, the first sodium‑glucose co‑transporter‑2 inhibitor approved by the USA FDA, has been shown to have a significant effect on cardiovascular damage caused by diabetes. However, it has not been reported whether it can resist THP‑induced cardiotoxicity. The aim of the present study was to investigate the effect of canagliflozin on THP‑induced cardiotoxicity and its mechanism. A rat model of cardiotoxicity induced by THP was established and canagliflozin treatment was performed at the same time. The changes of electrocardiography, cardiac coefficient and echocardiogram were observed. The levels of lactate dehydrogenase, brain natriuretic peptide, creatine kinase MB, cardiac troponin T, superoxide dismutase (SOD) and malondialdehyde were detected. The expression of SOD2, NADPH oxidase 2, pro/cleaved‑caspase‑ and Bcl‑2/Bax were evaluated by western blotting. The primary culture of cardiomyocytes was prepared to explore the effect

Topics: Animals; Brain; Canagliflozin; Cardiotonic Agents; Cardiotoxicity; Creatine Kinase, MB Form; Disease Models, Animal; Doxorubicin; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardium; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.

Topics: Animals; Cardiotoxicity; Doxorubicin; Mice; MicroRNAs; Myocytes, Cardiac; Proto-Oncogene Proteins c-jun; Rutin; Signal Transduction

One of the common adverse reactions to anthracyclines, a group of chemotherapeutics, is cardiotoxicity. Cancer patients receiving anthracycline-based chemotherapeutic regimens often discontinue treatment due to cardiotoxicity. How to prevent and reduce the cardiotoxicity of anthracyclines is one of the hot topics in the field of onco-cardiology. Traditional Chinese medicine can reduce the toxic side effects of chemotherapeutics. The present study aimed to investigate the protective effect of Qishen Huanwu capsule (QSHWC) on pirarubicin (THP)-induced myocardial injury in rats and the underlying mechanisms.. Forty-eight male Sprague-Dawley (SD) rats were randomly divided into six groups: control group, THP, low-dose QSHWC, moderate-dose QSHWC, high-dose QSHWC, and LY294002 [phosphatidylinositol 3-kinase (PI3K) inhibitor] (n=8 each). Echocardiographic examination was performed to examine heart structure and function. Hematoxylin and eosin (HE) staining was conducted to examine histopathological changes in myocardial tissue. Immunofluorescence staining was carried out to examine the expression of the autophagosome-specific marker protein microtubule-associated protein 1 light chain 3 (LC3). Western blot was performed to analyze the expression of LC3-I, LC3-II, PI3K, phosphorylated (p)-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR), and p-mTOR.. Compared with the control group, the THP group had a higher left ventricular end-systolic diameter (LVESD), lower left ventricular ejection fraction (LVEF), lower left ventricular fractional shortening (LVFS), and inferior heart function. In addition, compared with the control group, the THP group had significantly higher LC3 protein expression, a significantly higher LC3-II/LC3-I ratio (P<0.05), and significantly lower p-PI3K, p-Akt, and p-mTOR (P<0.05). QSHWC attenuated the THP-induced decline in heart function, downregulated LC3 protein in rat myocardial tissue, decreased the LC3-II/LC3-I ratio, and increased p-PI3K, p-Akt, and p-mTOR. In the LY294002 group, the above effects of QSHWC were reversed.. QSHWC alleviated THP-induced myocardial injury. The underlying mechanism was related to the activation of the PI3K/Akt/mTOR pathway and the mitigation of the excessive autophagy of cardiomyocytes caused by THP.

Topics: Animals; Cardiotoxicity; Doxorubicin; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Stroke Volume; TOR Serine-Threonine Kinases; Ventricular Function, Left

Cancer is the leading cause of deaths around the world, especially in low- and middle- income countries. Pirarubicin (THP) is an effective drug for treatment of cancer, however, there still exists cardiotoxic effects of THP. Rutin is a kind of antioxidative compound extracted from plants, and might be a protective compound for cardiomyocytes. Phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is critical for cellular survival, proliferation and metabolism, and thus we speculated rutin might perform a protective role in cardiomyocytes via PI3K/AKT/mTOR signaling pathway. And in this experiment, we first established a cardiotoxicity model of THP in mice model and cell models, and then found that rutin treatment could increase the proliferation of cells at low concentration. Then we explored the possible mechanism of the protective effect of rutin using Western blotting, quantitative polymerase chain reaction (qPCR) and ELISA methods, and found that the activation of PI3K/AKT/mTOR/nuclear factor-κB (NF-κB) signaling pathway was increased, and expression of downstream molecules involved in antioxidative stress were also increased. We further noticed that concentration of angiogenesis promoting factors were also increased in medium of cultured cells. Thus, we speculated that rutin could increase the activation of PI3K/AKT/mTOR signaling pathway, further decrease the oxidative stress level via increasing the expression of antioxidative stress enzymes with the increasing concentration of angiogenesis promoting factors, resulting in the protective role in cardiomyocytes and cardiac function.

Topics: Animals; Cardiotoxicity; Cardiotoxins; Doxorubicin; Male; Mice; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rutin; Signal Transduction; TOR Serine-Threonine Kinases

Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity.

Topics: Animals; Antioxidants; Apocynum; Apoptosis; Cardiotoxicity; Creatine Kinase; Doxorubicin; Drugs, Chinese Herbal; Humans; Male; Malondialdehyde; Natriuretic Peptide, Brain; Plant Leaves; Rats; Rats, Wistar; Superoxide Dismutase; Troponin