Doxorubicin (Dox) is an effective anti-cancer drug with severe reported cardiotoxicity. Cardiovascular risks associated with present cancer therapeutics demand urgent attention. There has been a growing interest in naturally occurring compounds to improve the therapeutic index as well as prevent non-tumour tissues from sustaining chemotherapy-induced damages. In the present study, the effects of curcumin, a polyphenol isolated from Curcuma longa and well known for its anti-oxidative, anti-cancerous and anti-inflammatory properties, was studied in relation to the Dox-induced cardiotoxicity. As literature suggests conflicting role of curcumin in Dox-induced cardiotoxicity, concentration- and time-dependent studies were conducted to study the different curcumin effects. H9C2 cardiomyoblasts were used in the study and cell viability assays were done to study Dox-induced cellular death. Drug uptake assay for Dox was performed followed by cellular growth inhibition analysis by FACS Calibur. Morphological alterations, intracellular ROS levels and mitochondrial integrity were observed by fluorescent-based microscopic studies. Catalases and superoxide dismutase-inbuilt anti-oxidant enzyme activities were studied, and it was observed that Dox-dependent cardiotoxicity occurs through ROS overproduction by exaggerating the inbuilt anti-oxidant mechanism. Expression analysis for cell death and ROS markers-BCl2, Bax, SOD, catalase-was investigated by semi-quantitative RT-PCR, and the Dox-induced stress on cardiac cells was confirmed. Initiator and effector caspases activity analysis also confirmed these findings. Our study proposes that curcumin exerts time-dependent responses on Dox-induced cardiotoxicity, where parallel treatment potentiates and pre-treatment suppresses the Dox-induced toxicity in H9C2 cardiomyoblasts. In conclusion, pre-treatment of curcumin suppresses the Dox-induced cardiotoxicity and holds a great potential as future cardio-oncological therapeutics.

中文翻译：

---

治疗方式决定姜黄素对阿霉素诱导的成肌细胞毒性的反应。

阿霉素（Dox）是一种有效的抗癌药物，具有严重的心脏毒性。与当前的癌症治疗方法有关的心血管风险需要紧急关注。天然存在的化合物对改善治疗指数以及防止非肿瘤组织维持化学疗法诱导的损害的兴趣日益浓厚。在本研究中，研究了姜黄素（一种从姜黄中分离出来的多酚，以其抗氧化，抗癌和抗炎特性而闻名）与Dox诱导的心脏毒性的关系。由于文献表明姜黄素在Dox诱导的心脏毒性中起冲突作用，因此进行了浓度和时间依赖性研究来研究姜黄素的不同作用。H9C2心肌母细胞用于研究，并进行细胞活力测定以研究Dox诱导的细胞死亡。进行Dox的药物吸收测定，然后通过FACS Calibur进行细胞生长抑制分析。通过基于荧光的显微镜研究观察到形态学改变，细胞内ROS水平和线粒体完整性。研究了过氧化氢酶和超氧化物歧化酶内置的抗氧化酶活性，并观察到通过夸大内置的抗氧化机理，ROS过量产生会产生Dox依赖性心脏毒性。通过半定量RT-PCR研究了细胞死亡和ROS标志物-BCl2，Bax，SOD，过氧化氢酶的表达分析，并确认了Dox诱导的对心脏细胞的应激。引发剂和效应子胱天蛋白酶活性分析也证实了这些发现。我们的研究提出，姜黄素对Dox诱导的心脏毒性具有时间依赖性，在这种情况下，平行治疗会增强作用，而预处理会抑制Dox诱导的H9C2心肌母细胞毒性。总之，姜黄素的预处理可抑制Dox引起的心脏毒性，并具有巨大的潜力，可作为未来的心脏肿瘤治疗剂。