Energy Metabolism Profile in Hepatocellular Carcinoma Cells Considering the Synergism Between Melatonin and Cisplatin

• Grant number: 23/10884-5
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Fábio Rodrigues Ferreira Seiva
• Grantee: Fábio Rodrigues Ferreira Seiva
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Luiz Gustavo de Almeida Chuffa ; Willian Fernando Zambuzzi
• Associated scholarship(s): 24/14377-3 - Effects of the Association between Melatonin and Cisplatin on Energy Metabolism in an Experimental Model of Hepatocellular Carcinoma, BP.DR

Abstract

The incidence of Hepatocellular Carcinoma (HCC) has been increasing in several countries over the years. In Brazil, a total of 12,674 cases and 12,139 deaths were registered in 2020. Globally, there were 905,677 new cases of HCC diagnosed in 2020, with an estimated mortality rate of 830,180. HCC is currently the sixth most common type of cancer worldwide and ranks as the third leading cause of death in absolute terms. The primary risk factors for HCC include viral infections such as hepatitis B and C, excessive alcohol consumption, aflatoxins, and non-alcoholic steatohepatitis. Although the prevalence of hepatitis infections is decreasing globally, the incidence of HCC is expected to rise due to the increasing prevalence of metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Tumour cells exhibit distinct characteristics, including a high replication rate, immune system evasion, invasion and metastasis capabilities, immortality, production of angiogenic stimuli, and reprogramming of energy metabolism. This metabolic reprogramming is associated with genetic alterations and cellular interactions that induce complex changes in glucose, lipid, and amino acid metabolism pathways, facilitating tumour development and progression. A well-known phenomenon observed in cancer cells is the Warburg effect, wherein cancer cells preferentially utilize the glycolytic pathway, even under aerobic conditions, to meet their energy and biosynthesis requirements. Additionally, amino acid and lipid metabolism may also undergo alterations in cancer.Currently, the treatment of HCC poses significant challenges, and therapeutic options are limited. Melatonin, a lipophilic indoleamine with systemic and cellular effects, has been investigated as a potential therapy for various types of cancer, including HCC. Melatonin has exhibited antiproliferative, anti-inflammatory, apoptosis-promoting, and antimetastatic effects on tumour cells. Recent studies have focused on elucidating the effects of melatonin on the modulation of tumour cell energy metabolism, including lactate metabolism, NAD+ and reactive oxygen species production. Although the combination of melatonin with cisplatin has been proposed, the mechanisms through which melatonin synergizes with classical chemotherapeutics and its impact on the energy metabolism of HCC cells remain incompletely understood. This research project aims to investigate the effects of melatonin, both alone and in combination with cisplatin, on metabolic pathways in HCC cells. The analysis will encompass protein expression levels, and enzymatic activity associated with energy metabolism, as well as the effects on oxidant/antioxidant status and cell death mechanisms. Furthermore, this project seeks to generate actionable knowledge, facilitate student training, and reinforce the research focus on energy metabolism and tumour cells. (AU)

Scientific publications

(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)

SEIVA, FABIO RODRIGUES FERREIRA; AGNEIS, MARIA LUISA GONCALVES; DE ALMEIDA, MATHEUS RIBAS; CAPUTO, WESLEY LADEIRA; DE SOUZA, MILENA CREMER; DAS NEVES, KAROLINY ALVES; OLIVEIRA, ERIKA NOVAIS; JUSTULIN JR, LUIS ANTONIO; CHUFFA, LUIZ GUSTAVO DE ALMEIDA. In Silico Analysis of Non-Conventional Oxidative Stress-Related Enzymes and Their Potential Relationship with Carcinogenesis. ANTIOXIDANTS, v. 13, n. 11, p. 19-pg., 2024-11-01. (23/10884-5)