Kamal Razavi-Azarkhiavi1, Mahmoud Reza Jaafari2,3, Khalil Abnous4, Bibi Marjan Razavi1, Amir Hossein Jafarian5, Faezeh Vahdati Hassani1, Kobra Shirani1, Gholamreza Karimi6. 1. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. 2. Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. 3. Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. 4. Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box, 1365-91775, I.R., Mashhad, Iran. 5. Cancer Molecular Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 6. Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box, 1365-91775, I.R., Mashhad, Iran. KarimiG@mums.ac.ir.
Abstract
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. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX).
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. Graphical Abstract The cardiotoxic mechanism of doxorubicin (DOX) and pegylated liposomal DOX (PL-DOX).
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