Effectiveness of cancer therapies targeting Sirtuins: is it dependent on Heme Oxygenase-1 modulation?

• Grant number: 24/23586-5
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: September 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Patricia Chakur Brum
• Grantee: Gabriel Albanese Kafouri
• Supervisor: Leo Edmond Otterbein
• Host Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 23/17631-5 - PRO-TUMORAL EFFECT OF BETA-ADRENERGIC RECEPTOR ACTIVATION AND ITS RELATIONSHIP TO THE SIRTUINS PATHWAY AND MODULATION BY EXERCISE MIMETIC, BP.IC

Abstract

Cancer is a large group of diseases and one of the leading global public health issues, characterized by uncontrolled growth of abnormal cells capable of invading adjacent tissues and forming metastases. Despite recent advances, available treatments remain limited, underscoring the need for a deeper understanding of this group of diseases, especially at the molecular level, to develop new therapeutic strategies and enhance the efficacy of existing approaches. In this context, Sirtuins (SIRTs), a family of histone deacetylase enzymes, play a significant and complex role in the initiation and progression of cancer, exhibiting abnormal expression patterns in different tumor types. Drugs that modulate the activity of these proteins have shown great therapeutic potential. However, due to the functional heterogeneity of SIRTs, the molecular mechanisms responsible for their antitumor effects are still poorly understood. In parallel, the antioxidant enzyme Heme oxygenase-1 (HO-1) also plays an important role in tumor survival. Indeed, the overexpression of HO-1 in tumors is associated with increased aggressiveness, poor prognosis, and greater therapeutic resistance, as this enzyme provides protection against oxidative damage, leading to increased resistance to cell death. Recently, a relationship between SIRTs and HO-1 has been demonstrated in some pathophysiological contexts, including cancer. However, the role of HO-1 as a molecular mediator of the therapeutic effects of SIRTs-modulating drugs has not yet been investigated. Therefore, this project will investigate whether the antitumor effects of drugs modulating SIRTs activity are mediated by the regulation of HO-1 expression in cancer cells. Investigations like this are crucial, as characterizing the molecular mechanisms underlying the beneficial effects of these therapies provides a foundation for making them even more effective in specific contexts, thereby increasing their clinical application.