Razavi-Azarkhiavi Kamal, Jaafari Mahmoud Reza, Abnous Khalil, Razavi Bibi Marjan, Jafarian Amir Hossein, Hassani Faezeh Vahdati, Shirani Kobra, Karimi Gholamreza
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Pharm Res. 2017 Sep;34(9):1849-1856. doi: 10.1007/s11095-017-2194-3. Epub 2017 May 30.
MicroRNAs (miRs) are a group of small non-coding RNAs that regulate transcriptional or post-transcriptional gene expression. The aim of the present study was to investigate the role of miR -1, -21 and -145 and their targets in cardiotoxicity-induced by DOX and pegylated liposomal DOX.
BALB/c mice subjected to subcutaneous injection of C-26 tumor cells. Eight days after tumor inoculation, animals were divided into 6 groups: control, liposome, DOX (6 and 9 mg/kg) and PL-DOX (6 and 9 mg/kg). The formulations were administered one time per week for four weeks. 24 h after the last injection, mice were sacrificed; blood and heart samples were taken. Western blot analysis was done on protein extracts to investigate the expression of cardiac caspase-3, -8, Bax, Bcl2, Programmed cell death 4 (PDCD4) and BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3). The expression levels of miR -1, -21 and -145 were also evaluated by quantitative real-time PCR.
Mice treated with both DOX formulations showed a marked inhibition in tumor growth. Western blot analysis indicated that the expression level of cardiac caspase-3, caspase-8, Bax and BNIP3 were up-regulated due to DOX injection (9 mg/kg). Exposure of mice with DOX resulted in a significant increase in cardiac miR-1 and miR-21 expression level. PL-DOX treatment did not change the proteins and miRs expression.
The results suggest that miR -1, -21 and -145 may involve in cardiotoxicity induced by DOX. Evaluation of miRs signaling pathways might be of potential value for toxicity assessment of new formulations. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX).
微小RNA（miR）是一类调节转录或转录后基因表达的小非编码RNA。本研究旨在探讨miR-1、-21和-145及其靶点在阿霉素（DOX）和聚乙二醇化脂质体阿霉素诱导的心脏毒性中的作用。
将BALB/c小鼠皮下注射C-26肿瘤细胞。肿瘤接种8天后，将动物分为6组：对照组、脂质体组、DOX（6和9mg/kg）组和聚乙二醇化脂质体阿霉素（PL-DOX，6和9mg/kg）组。制剂每周给药1次，共4周。最后一次注射后24小时，处死小鼠；采集血液和心脏样本。对蛋白质提取物进行蛋白质印迹分析，以研究心脏半胱天冬酶-3、-8、Bax、Bcl2、程序性细胞死亡4（PDCD4）和BCL2/腺病毒E1B 19kDa相互作用蛋白3（BNIP3）的表达。还通过定量实时PCR评估miR-1、-21和-145的表达水平。
用两种DOX制剂治疗的小鼠肿瘤生长均受到显著抑制。蛋白质印迹分析表明，由于注射DOX（9mg/kg），心脏半胱天冬酶-3、半胱天冬酶-8、Bax和BNIP3的表达水平上调。用DOX处理小鼠导致心脏miR-1和miR-21表达水平显著增加。PL-DOX治疗未改变蛋白质和miR的表达。
结果表明，miR-1、-21和-145可能参与DOX诱导的心脏毒性。评估miR信号通路可能对新制剂的毒性评估具有潜在价值。图摘要阿霉素（DOX）和聚乙二醇化脂质体阿霉素（PL-DOX）的心脏毒性机制。
