Ferroptosis and the chemotherapy drug resistance in oral squamous cell carcinoma: mechanisms of action and Kaempferol effects on drug sensitization

• Grant number: 25/01323-5
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Ricardo Della Coletta
• Grantee: Ricardo Della Coletta
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
• Associated researchers: Edgard Graner

Abstract

Oral squamous cell carcinoma (OSCC) is a heterogeneous and aggressive tumor, often diagnosed in advanced stages, where the treatment requires the administration of chemotherapy. Despite advances, several challenges can occur during treatment, including the acquisition of resistance to chemotherapy drugs. In this sense, a complete understanding of the mechanisms associated with chemoresistance is of utmost importance, as well as identifying ways to reverse this state acquired by tumor cells. Cisplatin, 5-fluorouracil and docetaxel are the main drugs used in the treatment of OSCC and though they are initially successful in controlling the tumors, resistance to one or more of these drugs is observed in at least one third of the patients. Among the mechanisms associated with the drug resistance is reduced sensitivity to signals that promote cell death, including ferroptosis, a type of non-apoptotic programmed cell death dependent on iron accumulation and lipid peroxidation. The aim of this study is to investigate the role of ferroptosis in the process of drug resistance (cisplatin, 5-fluorouracil and docetaxel) in OSCC cells, and to determine whether Kaempferol (KMP), a flavonoid with important antitumor effects, sensitizes tumor cells to the action of the drugs via activation of ferroptosis. OSCC cells, parental (sensitive) and drug-resistant, will be used in this study. After treatments with drugs (at their inhibitory concentration of 50% of cell viability - IC50), KMP (40 µM) or the combination of drugs and KMP, the cells will be subjected to a series of assays that characterize the ferroptosis, including cell viability assay, quantification of iron ions, quantification of lipid peroxidation (malondialdehyde), quantification of glutathione, quantification of reactive oxygen species, and quantification of the expression and production of GPX4, SLC7A11 and ACSL4. Agonists and antagonists of ferroptosis will be employed to confirm the involvement of ferroptosis during drug action, in chemoresistance and in sensitization promoted by KMP. This study is expected to demonstrate the participation of ferroptosis in the process of resistance, and to determine whether the antitumor activity of KMP occurs via induction of ferroptosis, especially in the drug-resistant cells. (AU)