Effects of the Association between Melatonin and Cisplatin on Energy Metabolism in an Experimental Model of Hepatocellular Carcinoma

• Grant number: 24/14377-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Fábio Rodrigues Ferreira Seiva
• Grantee: Wesley Ladeira Caputo
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated research grant: 23/10884-5 - Energy Metabolism Profile in Hepatocellular Carcinoma Cells Considering the Synergism Between Melatonin and Cisplatin, AP.R

Abstract

According to INCA data, the number of liver cancer cases in Brazil has increased every year since 1979. Although it's not one of the most common types in our country, in 2019 it ranked sixth and eighth in terms of mortality rates in men and women, respectively. The most common type of liver cancer is hepatocellular carcinoma (HCC), whose risk factors include hepatitis virus infections, alcohol abuse and cirrhosis. It is important to note that another risk factor is metabolic fatty liver disease, which is closely linked to obesity. As the number of obese or overweight people has reached epidemic proportions, a significant increase in the number of HCCs is expected in the coming years. Current therapeutic alternatives are not resolutives and can lead to chemoresistance and high recurrence rates, leaving liver transplantation as the only curative option for patients. The search for new therapies to improve the prognosis of patients with HCC is therefore mandatory. In this scenario, melatonin has emerged as a promising alternative. Melatonin (Mel) has antiproliferative, anti-angiogenic, pro-apoptotic and immunomodulatory properties in tumour cells. Mel may act as a therapeutic adjuvant, reducing side effects and increasing sensitivity to chemotherapy drugs. However, the exact mechanisms involved in the effects of Mel on HCC cells remain to be elucidated. One of the characteristics of tumour cells is their ability to obtain nutrients in an unfavourable microenvironment and to optimise their use to provide energy and biomass to maintain their viability and proliferation. The aim of this project is to investigate in detail the energy metabolism and some of the mechanisms involved in the treatment with Mel and Mel associated with the chemotherapeutic drug cisplatin. This project is divided into two successive stages. In the first stage, different cell lines will be subjected to different therapeutic regimens; this in vitro approach will make it possible to elucidate the metabolic pathways that respond to the treatments, as well as suggesting possible modes of action of Mel alone and in combination. In a second step, the treatments will be tested in rats with chemically induced HCC. Systemic toxicity parameters and potential adverse effects will be assessed, as well as survival rates and liver tissue metabolomics analyses. The aim is to identify deregulated pathways in HCC and to assess the impact of complementary treatment with melatonin. As well as contributing to the state of the art in HCC and complementary therapies, the study aim to add to the literature and possibly suggest future clinical trials with melatonin.