Senotherapeutic potential of drugs and polyphenols combinations

• Grant number: 20/07256-4
• Support Opportunities: Regular Research Grants
• Duration: August 01, 2021 - July 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Alessandra Gambero
• Grantee: Alessandra Gambero
• Host Institution: ESC CIENCIAS VIDA/PUCCAMPINAS

Abstract

The elderly population with or without associated comorbidities, such as diabetes and cardiovascular disease is the most vulnerable group to COVID-19 mortality. Cell senescence is the process of cell aging that increases during the progression of chronic diseases (such as diabetes) and with aging, resulting in irreversible arrest of the cell cycle controlled by the p53 / p21 and p16 / Rb pathways and increased production of pro-inflammatory cytokines (mainly IL-1² and IL-6), a phenomenon known as "senescence-associated secretory phenotype, SASP". An imbalance in the activation of the renin-angiotensin system (RAS) is also observed in senescent cells, which can contribute to the inflammatory and thrombotic conditions observed in patients with COVID-19. In addition, senescent cells have a pro-fibrotic secretome, and pulmonary fibrosis is also identified as a problem of pulmonary disease in patients with COVID-19. The identification of compounds that can control the senescence process has become a priority since they can have immense therapeutic potential. Drugs such as metformin, hydroxychloroquine and rapamycin, and azithromycin and dasatinib can act as modifiers of senescent and senolitic markers, respectively. Some senolitic drugs are in clinical trials in lung diseases, such as the combination dasatinib+quercetin, the latter a polyphenol that has shown synergistic effects in this combination. Senostatics are also currently being studied as a means of controlling metabolic diseases. Thus, this project aims to evaluate the senolytic, senostatic and/or antifibrotic potential in senescent human lung cells of combinations between drugs (dasatinib, azithromycin, metformin, rapamycin and hydroxychloroquine) and polyphenols (caffeic acid, ferulic acid, catechin and epicatechin) that can be isolated from Brazilian products with national technology. The most promising combination will be tested in vivo in elderly mice with acute lung injury (preclinical phase). Data from this project may reveal new therapeutic possibilities in the management of diseases that have unfavorable outcomes in the elderly population and with metabolic comorbidities, such as COVID-19. (AU)