Cellular organelles as pharmacological targets of palladium-oxime complexes: overcoming resistance of bone tumors to cisplatin, doxorubicin, and methotrexate by reducing ATP supply to efflux pumps

• Grant number: 24/18491-5
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Claudia Bincoletto Trindade
• Grantee: Claudia Bincoletto Trindade
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Adelino Vieira de Godoy Netto

Abstract

The aim of this project is to evaluate the efficacy of palladium-oxime complexes in targeting specific cellular organelles, such as lysosomes and mitochondria, to overcome drug resistance in bone tumors, particularly osteosarcomas. These tumors exhibit significant resistance to traditional drugs like cisplatin, doxorubicin, and methotrexate, presenting a major challenge in oncological treatment. Palladium-oxime complexes are being developed with the purpose of interacting with lysosomes and mitochondria to reduce the supply of ATP required for the operation of efflux pumps. These pumps, such as P-gp1, are responsible for expelling drugs from cancer cells, contributing to resistance. By decreasing the availability of ATP, it is expected to weaken the action of these pumps, allowing the drugs to remain in the cancer cells longer and thereby enhancing their effectiveness. The project also explores the involvement of microRNAs, as well as the processes of autophagy and mitophagy, which are directly linked to lysosomes and mitochondria, respectively. It is worth noting that our group has a long-standing history of research on cyclopalladated complexes, and the data obtained so far consistently demonstrate the affinity of these compounds for mitochondria and lysosomes, with promising antitumor results. In vitro studies will include assessments of the efficacy of these complexes in apoptosis (cell death) assays, ferroptosis, and the inhibition of cell proliferation, focusing on their impact on the clonogenic capacity of tumor cells. Additionally, the most promising compounds will undergo in vivo toxicity tests using the C. elegans model, which is more ethical and easier to handle, avoiding the use of mammals in the initial stages. Furthermore, the project holds significant potential for training and mentoring undergraduate and graduate students, making a substantial contribution to academic development. The goal is to open new perspectives in the treatment of drug-resistant bone tumors, offering an innovative approach to overcoming the resistance associated with traditional chemotherapeutic agents. Finally, the project aims to patent new molecules, which may drive innovation and the development of advanced therapies in the oncological field. (AU)