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| Author(s): |
Leonardo da Cunha Menezes Souza
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Botucatu. 2019-03-08. |
| Institution: | Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu |
| Defense date: | 2019-02-01 |
| Advisor: | Daisy Maria Fávero Salvadori |
| Abstract | |
The cardiotoxicity induced by doxorubicin (DOX), anthracycline isolated from the actinobacteria Streptomyces peucetius, and widely used as an antineoplastic drug, is one of the most important pathophysiological events that limit its clinical application. However, all the mechanisms involved in this toxicity are not fully understood. One hypothesis is that the aldehydes generated by DOX act on mitochondrial membranes, modifying the redox state and proting adducts with proteins. DOX activities on other cellular components, such as ribonucleic acids, are also possible mechanisms of toxicity. Several strategies have been used to reduce the DOX adverse effects. One of them is the identification of compounds that can protect cells against cytotoxic. Alda-1, which belongs to a group of chaperones and is an agonist of the mitochondrial aldehyde dehydrogenase (ALDH2), has been tested to reduce the adverse effects of metabolites and radicals generated by DOX. To investigate other possible DOX mechanisms of action, and the cardioprotective activity of Alda-1, this study was designed using two different approaches: in vivo, with male Wistar rats submitted to acute and chronic treatments; and, in vitro, in mice fibroblasts and cybrids with ND5 (gene that encodes the mitochondrial Complex I subunit) mitochondrial gene heteroplasmy. The expression profiling of genes related to beta oxidation pathways, Bax, Bcl-2, C1QBP, ALDH2 and miR34a microRNA (ALDH2 expression regulator), and the lipoperoxidation process were investigated in cardiomyocytes of rats treated with DOX, or with DOX plus Alda-1. In vitro, the effects of the two compounds on cell viability, mitochondrial structure and cardiolipin molecular species profile, were investigated. In addition, it was assessed whether heteroplasmy levels could interfere on DOX toxic activity. The results confirmed the DOX effect on lipid profile, increasing triglycerides and VLDL concentration. Simultaneous treatment with Alda-1 decreased such effect. Gene expression analyses revealed the overexpression of Fabp4, Slc27a2, Bcl-2 and C1QBP in cardiomyocytes of rats treated with DOX (acute treatment). Again, the Alda-1 simultaneous administration was able to modulate the changes on gene expressions. In vitro, DOX promoted changes in mitochondrial heteroplasmy towards a mutant genotype, decreased cell viability and morphological changes in the mitochondrias. These events were reduced by the action of Alda-1. In conclusion, besides the known mechanisms of action, DOX was able to modulate genes involved in the fatty acids transportation and in oxidative stress pathways. Furthermore, DOX promoted changes in mitochondrial heteroplasmy. On the other hand, the results confirmed the protective effect of Alda-1 against the DOX toxic activity through its ability to reduce hyperlipidemia and gene expression. (AU) | |
| FAPESP's process: | 14/09740-0 - Cardiotoxicity induced by doxorubicin in Wistar rats and the cardioprotective potential of Alda-1 |
| Grantee: | Leonardo da Cunha Menezes Souza |
| Support Opportunities: | Scholarships in Brazil - Doctorate |