Palladium-oxime complexes as an alternative for the treatment of human osteosarcoma resistant to cisplatin, doxorubicin and methotrexate: role of mitochondria and lysosomes in cell death induction events

• Grant number: 24/06586-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2025
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Claudia Bincoletto Trindade
• Grantee: Thales Hebert Regiani Pereira
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Drug resistance, cell death evasion and metastasis are factors that contribute to the low disease-free survival rate in several tumors, including osteosarcoma. In previous studies (Pereira et. Al. Eur. J. Med. Chem. 2024) we demonstrated that a new class of organometallic complexes containing oximes called Pd-BPO(1) and Pd-BMO(2) are more cytotoxic than cisplatin (CDDP) for SaOS-2 and U2O2 osteosarcoma cells. Annexin-FITC/7-AAD staining demonstrated a greater potential for oxime complexes to induce cell death compared to CDDP. Compared to CDDP, only oxime complexes eradicated the clonogenicity of SaOS-2 cells after 7 days of treatment. The involvement of the lysosome-mitochondria axis in the cell death-inducing properties of oxime complexes was also verified using lysotracker red and TMRE (tetramethyl rhodamine, ethyl ester) and acridine orange, respectively. In vivo studies using C. elegans demonstrated that both complexes reduced body curvatures and pharyngeal pumping after 24 hours of treatment to the same extent as that induced by CDDP. Therefore, in this work, we will continue our studies with a view to obtaining a drug that can overcome the resistance of osteosarcoma cells to drugs such as CDDP, methotrexate and doxurubicin, which are used in the treatment of these tumors. After obtaining cells resistant to the three drugs separately and together, we will evaluate the participation of the lysosome-mitochondria axis in the processes of cell death through apoptosis, ferroptosis and necroptosis in the presence of palladium-oxime complexes. Proteins that confer cellular resistance, such as ABCs and the microRNAi miR-34a, will also be the focus of our studies. As a result, we hope to better understand the mechanisms involved in the antitumor actions of the palladium-oxime complexes described above in the process of multidrug resistance and also identify the role of mitochondria and lysosomes in these events. If successful, the next step would be to carry out preclinical trials with cells from Osteosarcoma patients through collaboration with hospitals where patients with these tumors are cared for and treated. (AU)