阿霉素心肌毒性机制研究进展

阿霉素属于蒽醌类抗肿瘤药,临床上用于白血病、淋巴瘤、乳腺癌等多种恶性肿瘤的治疗,且作用广谱,效果显著,但其所致心肌毒性不仅限制了其临床使用,也影响了患者的生活质量。因此,探讨阿霉素诱导心肌毒性的作用机制具有重要意义,本文就近年来阿霉素所致心肌毒性的作用机制研究做一综述。     

一氧化氮在阿霉素心脏毒性中的双重作用

蒽环类抗生素阿霉素（Doxombicin,DOX）是一种高效的抗肿瘤药物,主要用于治疗血液学疾病以及各种实体瘤。但因其引发多重生物化学通道的细胞损伤,进而导致严重的剂量依赖性心脏毒性作用,使其临床应用及治疗指数受到限制与影响。NO是与心脏病理生理学相关的重要生物信使分子,其在阿霉素心脏毒性中的重要作用受到了普遍的关注。本文通过查阅近年来的国内外有关文献,对于此焦点问题进行了分析总结。     

Protective effect of taurine against doxorubicin-induced cardiotoxicity in perfused chick hearts

The ability of taurine to protect the isolated heart against doxorubicin cardiotoxicity was examined. Chick hearts perfused for 20 min with medium containing 17 microM doxorubicin exhibited a decrease in contractility, an increase in resting tension and a dramatic depletion in tissue high energy phosphate content. Addition of 20 mM taurine to the perfusate attenuated the increase in resting tension and the decrease in myocardial adenosine triphosphate content induced by doxorubicin. The present study confirms our previous in vivo observations that taurine partially prevents doxorubicin-induced cardiotoxicity.     

Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin

Abstract

1.?The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin.

2.?Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats.

3.?Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin.

4.?Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart.

5.?These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.     

Noncoding RNAs in doxorubicin-induced cardiotoxicity and their potential as biomarkers and therapeutic targets

Anthracyclines,such as doxorubicin(DOX),are well known for their high efficacy in treating multiple cancers,but their clinical usage is limited due to their potential to induce fatal cardiotoxicity.Such detrimental effects significantly impact the overall physical condition or even induce the morbidity and mortality of cancer survivors.Therefore,it is extremely important to understand the mechanisms of DOX-induced cardiotoxicity to develop methods for the early detection of cytotoxicity and therapeutic applications.Studies have shown that many molecular events are involved in DOX-induced cardiotoxicity.However,the precise mechanisms are still not completely understood.Recently,noncoding RNAs(ncRNAs)have been extensively studied in a diverse range of regulatory roles in cellular physiological and pathological processes.With respect to their roles in DOX-induced cardiotoxicity,microRNAs(miRNAs)are the most widely studied,and studies have focused on the regulatory roles of long noncoding RNAs(lncRNAs)and circular RNAs(circRNAs),which have been shown to have significant functions in the cardiovascular system.Recent discoveries on the roles of ncRNAs in DOX-induced cardiotoxicity have prompted extensive interest in exploring candidate ncRNAs for utilization as potential therapeutic targets and/or diagnostic biomarkers.This review presents the frontier studies on the roles of ncRNAs in DOX-induced cardiotoxicity,addresses the possibility and prospects of using ncRNAs as diagnostic biomarkers or therapeutic targets,and discusses the possible reasons for related discrepancies and limitations of their use.     

Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats

The prevention of doxorubicin (DXR)-induced cardiotoxicity may be helpful to improve future DXR therapy. The aim of this study was to investigate the cardio-protective effects of caffeic acid phenethyl ester (CAPE), an antioxidant agent, on DXR-induced cardiotoxicity. Rats were divided into three groups and treated with saline, DXR and DXR + CAPE. Rats were treated with CAPE (10 micromol x kg(-1) day(-1) i.p.) or saline starting 2 days before a single dose of DXR (20 mg x kg(-1) i.p.). Ten days later, haemodynamic measurements were performed and the hearts were excised for biochemical analyses and microscopic examination. The heart rate and mean blood pressure were higher and the pulse pressure was lower in the DXR group than in the other two groups. The administration of DXR alone resulted in higher myeloperoxidase activity, lipid peroxidation and protein carbonyl content than in the other groups. The activities of superoxide dismutase and catalase were higher in DXR and DXR + CAPE groups than in the saline group. Rats in the DXR + CAPE group had increased catalase activity in comparison with the DXR group and high glutathione peroxidase activity in comparison with the other two groups. There was severe disruption of mitochondrial fi ne structure in the electron microscopy of the DXR group. In contrast, myocardial microscopy appeared nearly normal in the DXR + CAPE group (as de fi ned at the electron microscopic level). In light of these in vivo haemodynamic, enzymatic and morphological results, we conclude that CAPE pretreatment significantly attenuated DXR-induced cardiac injury, possibly with its antioxidant effects.     

MicroRNA-34a-5p as a promising early circulating preclinical biomarker of doxorubicin-induced chronic cardiotoxicity

Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early-onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR-34a-5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL-treated controls and showed a statistically significant dose-related response. The trend in plasma miR-34a-5p expression levels during DOX exposures also correlated with a significant dose-related increase in cardiac expression of miR-34a-5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR-34a-5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR-34a-5p as a potential early circulating marker of early-onset DOX cardiotoxicity. In addition, higher expression of miR-34a-5p (FDR < 0.1) in plasma and heart compared with SAL-treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed-onset cardiotoxicity model, indicated its potential as an early biomarker of delayed-onset cardiotoxicity.     

西红花酸对多柔比星致大鼠心脏毒性的影响

目的：研究西红花酸减轻多柔比星心脏毒性的作用并探讨其机制。方法：建立多柔比星损伤大鼠心脏模型，灌胃给予西红花酸，观察动物心电图变化，测定血清乳酸脱氢酶（LDH）、肌酸激酶（CK）、超氧化物歧化酶（SOD）、全血谷胱甘肽过氧物酶（GSH—Px）和丙二醛（MDA）的变化，用光镜及透射电镜观察心肌的病理改变。结果：西红花酸可以有效改善多柔比星诱导的大鼠心电图异常，如QRS复合波变宽、Q＆T间期延长、T波高耸以及心率变缓（P〈0．05），阻滞多柔比星引起的总SOD，Cu-Zn-SOD，全血GSH—Px活性降低和LDH，CK活性升高及MDA的升高（P〈0．05）；改善心肌超微结构的病理变化。结论：西红花酸可以减轻多柔比星的心脏毒性。     

免疫调节相关的信号转导通路研究现状

随着现代分子生物学的迅速发展及其在免疫学研究中的广泛应用,人们已发现多种信号转导通路与免疫调节相关。目前研究较多的主要有TLRs信号通路、JAK-STAT信号通路、T细胞活化通路、B细胞活化通路等。这些信号转导通路任何环节发生异常均会导致疾病发生。     

生脉注射液预防多柔比星相关性心脏毒性反应的临床观察

目的探讨生脉注射液对多柔比星(阿霉素)相关性心脏毒性的保护作用。方法59例恶性肿瘤患者,随机地分成观察组和对照组两组。观察组30例,在以ADM为主的一线方案化疗前3天予生脉注射液50ml加入5%葡萄糖注射液250ml中静脉滴注,每日一次,两周一疗程;对照组29例,于化疗前3天开始服用VitE每次100mg,每日两次,辅酶Q10每次20mg,每日三次,两周一疗程。治疗前后检查心电图,超声心动图中左心室舒张末期内径(LVIDD)、左心室收缩末期内径(LVISD)、舒张早期与晚期充盈速度比值(A/E)、射血分数(EF)、短轴缩短率(FS)等各项指标。结果在本组ADM化疗后,观察组与对照组间,虽然EF差异无显著性(P>0.05),但心电图异常改变及LVIDD、LVISD、A/E、EF、FS的差异有显著性(P<0.05)。结论生脉注射液是预防和减轻ADM引起的急性心脏毒性的较为理想的药物,对慢性心脏毒性发生的减轻也有益。