Metabolic effects of doxorubicin on the muscle and adipose tissue: do exercise and...
| Grant number: | 19/09854-9 |
| Support type: | Regular Research Grants |
| Duration: | December 01, 2019 - November 30, 2021 |
| Field of knowledge: | Biological Sciences - Physiology - General Physiology |
| Principal Investigator: | José Cesar Rosa Neto |
| Grantee: | José Cesar Rosa Neto |
| Home Institution: | Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
Abstract
Cancer has shown epidemic levels bringing considerable economic and social impact in modern society. Nowadays, cancer is the second cause of death in the world, with a high probability to become the principal cause of death in the next decade. Although several advances in the treatment, the life expectancy and quality of life of the patient can be affected by the chemotherapy. Our group has demonstrated that doxorubicin, the main chemotherapy drug in clinical practice against the solid tumors, used isolated or in polychemotherapy, it shows devasting effects upon the metabolic regulation in adipose tissue and skeletal muscle. These deleterious effects can induce several signs and symptoms that mimic the cancer cachexia, leading to a reduction in quality and life expectancy. Thus, it is essential the investigation about coadjuvants treatments that can reduce the side effects of doxorubicin without efficacy impairment. Adipose tissue is severely affected by doxorubicin causing a huge inhibition of PPAR-gamma. This reduction affects several metabolic processes in adipose tissue, such as lipogenesis, adipogenesis, glucose uptake, and adipokines production. Moreover, recently it was demonstrated that this drug increases PPAR-alpha dependent manner lipolysis. These effects induce severe lipotoxicity. Thus, we intend to administrate the pioglitazone, an activator of PPAR-gamma, as well as a genetically modified model, with a partial deletion of PPAR-alpha, to elucidate the role of these transcription factors as the target to mitigate the lipotoxicity generated by doxorubicin treatment. Our aim is to evaluate the role of PPAR-alpha and PPAR-gamma upon the lipotoxicity generated by one cycle (5 weeks, 3 mg/kg body weight, once a week) of doxorubicin. We will investigate the role of co-treatment with pioglitazone associated with doxorubicin, or the partial deletion of PPAR-alpha can mitigate the deleterious effects of doxorubicin in lipolysis, lipogenesis, adipogenesis, glucose uptake, inflammation, adipokines and the macrophage phenotype infiltrated in subcutaneous adipose tissue. Finally, if our hypothesis was confirmed we intend to perform an additional experiment with the treatment of doxorubicin in tumor-bearing mice in order to averiguate if these interventions are able to keep the efficacy of the chemotherapy treatment and the possible increase on life expectancy. (AU)