Effect of doxorubicin upon the adipose tissue: elucidation the role of PPARs family

• Grant number: 19/09854-9
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: José Cesar Rosa Neto
• Grantee: José Cesar Rosa Neto
• Host 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)

Scientific publications

(10)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE SOUZA TEIXEIRA, ALEXANDRE ABILIO; LIRA, FABIO SANTOS; ROSA-NETO, JOSE CESAR. Aging with rhythmicity. Is it possible? Physical exercise as a pacemaker. Life Sciences, v. 261, NOV 15 2020. (15/16777-0, 16/01409-8, 19/09854-9, 18/24187-6)

ALVES DE LIMA, JR., EDSON; TEIXEIRA, ALEXANDRE ABILIO DE SOUZA; BIONDO, LUANA AMORIM; DINIZ, TIEGO APARECIDO; SILVEIRA, LOREANA SANCHES; COLETTI, DARIO; BUSQUETS RIUS, SILVIA; ROSA NETO, JOSE CESAR. Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy. CANCERS, v. 12, n. 11, NOV 2020. (15/17068-2, 13/09367-4, 19/01244-7, 19/09854-9)

DINIZ, TIEGO APARECIDO; DE LIMA JUNIOR, EDSON ALVES; TEIXEIRA, ALEXANDRE ABILIO; BIONDO, LUANA AMORIM; FERNANDES ROCHA, LUCAS ARIEL; VALADAO, IURI CORDEIRO; SILVEIRA, LOREANA SANCHES; CABRAL-SANTOS, CAROL; DE SOUZA, CAMILA OLIVEIRA; ROSA NETO, JOSE CESAR. Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-alpha signaling in obese mice. Life Sciences, v. 266, FEB 1 2021. (19/09854-9, 16/02696-0)

DE SOUZA TEIXEIRA, ALEXANDRE ABILIO; MINUZZI, LUCIELE GUERRA; LIRA, FABIO SANTOS; VIEIRA PEREIRA GONCALVES, ANA SOFIA; MARTINHO, ANTONIO; ROSA NETO, JOSE CESAR; TEIXEIRA, ANA MARIA. Improvement in the anti-inflammatory profile with lifelong physical exercise is related to clock genes expression in effector-memory CD4+T cells in master athletes.. EXERCISE IMMUNOLOGY REVIEW, v. 27, p. 17-pg., 2021-01-01. (19/10187-7, 19/09854-9, 16/01409-8, 18/24187-6, 15/16777-0, 18/19678-0, 19/25626-6)

TEIXEIRA, ALEXANDRE ABILIO S.; BIONDO, LUANA AMORIM; SILVEIRA, LOREANA S.; LIMA, EDSON A.; BATATINHA, HELENA A.; DINIZ, TIEGO A.; DE SOUZA, CAMILA OLIVEIRA; COMIN, JEFERSON; ROSA NETO, JOSE CESAR. Doxorubicin modulated clock genes and cytokines in macrophages extracted from tumor-bearing mice. CANCER BIOLOGY & THERAPY, JAN 2020. (15/16777-0, 19/09854-9, 16/01409-8)

BATATINHA, HELENA ANGELICA PEREIRA; KRUEGER, KARSTEN; ROSA NETO, JOSE CESAR. Thromboinflammation and COVID-19: The Role of Exercise in the Prevention and Treatment. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 7, p. 4-pg., 2020-12-18. (19/09854-9)

TEIXEIRA, ALEXANDRE ABILIO S.; BIONDO, LUANA AMORIM; SILVEIRA, LOREANA S.; LIMA, EDSON A.; BATATINHA, HELENA A.; DINIZ, TIEGO A.; DE SOUZA, CAMILA OLIVEIRA; COMIN, JEFERSON; ROSA NETO, JOSE CESAR. Doxorubicin modulated clock genes and cytokines in macrophages extracted from tumor-bearing mice. CANCER BIOLOGY & THERAPY, v. 21, n. 4, p. 10-pg., 2020-01-14. (15/16777-0, 16/01409-8, 19/09854-9)

ROSA-NETO, JOSE CESAR; SILVEIRA, LOREANA SANCHES. Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 24, DEC 2020. (19/09854-9, 19/09679-2)

BATATINHA, HELENA; TAVARES-SILVA, EDGAR; LEITE, GEOVANA S. F.; RESENDE, AYANE S.; ALBUQUERQUE, JOSE A. T.; ARSLANIAN, CHRISTINA; FOCK, RICARDO A.; LANCHA, JR., ANTONIO H.; LIRA, FABIO S.; KRUEGER, KARSTEN; et al. Probiotic supplementation in marathonists and its impact on lymphocyte population and function after a marathon: a randomized placebo-controlled double-blind study. SCIENTIFIC REPORTS, v. 10, n. 1, NOV 2 2020. (19/09854-9, 16/10561-8)

NETO, JOSE CESAR ROSA; CALDER, PHILIP C.; CURI, RUI; NEWSHOLME, PHILIP; SETHI, JASWINDER K.; SILVEIRA, LOREANA S.. The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 16, AUG 2021. (19/09854-9, 19/09679-2)