The Cardiotoxic Mechanism of Doxorubicin (DOX) and Pegylated Liposomal DOX in Mice Bearing C-26 Colon Carcinoma: a Study Focused on microRNA Role for Toxicity Assessment of New Formulations

Purpose 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. Methods 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. Results 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. Conclusion 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.