Funder: Non-profit organization "Climbers Against Cancer"

Period: 2024-2026.

Project leader: Dr. Ljubica Harhaji-Trajković, Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” — National Institute of the Republic of Serbia, University of Belgrade, Serbia

Team members from IBISS:
Dr. Nevena Zogović, Department of Neurophysiology IBISS
Dr. Ljubica Vučićević, Department of Neurophysiology IBISS
Dr. Maja Misirkić Marjanović, Department of Neurophysiology IBISS
Dr. Kristina Janjetović, Department of Neurophysiology IBISS
Dr. Ana Despotović, Department of Neurophysiology IBISS
Dr. Gordana Tovilović Kovačević, Department of Biochemistry IBISS

External advisors:
Dr. Mihajlo Bošnjak, Faculty of Medicine, University of Belgrade, Serbia
Dr. Milica Kosić, Faculty of Medicine, University of Belgrade, Serbia
Dr. Miloš Mandić, Faculty of Medicine, University of Belgrade, Serbia

Dr. Biljana Ristić, Institute for Medical Research, University of Belgrade

Project Website

Abstract

Metastatic melanoma relies on aerobic glycolysis to meet high energy demands. It’s enlarged, unstable lysosomes foster metastasis and drug resistance, yet create a vulnerability to lysosomal membrane permeabilization (LMP), cytosolic cathepsin leakage, and cell death. We will test the anti-melanoma efficacy of dual targeting of lysosomal fragility and hyperactive glycolysis. A375 human melanoma cells will be treated with LMP-inducing drugs (siramesine, mefloquine) combined with glycolysis inhibitors (2-deoxy-D-glucose, shikonin, dichloroacetate). We will use viability assays (crystal violet, LDH) to identify the most potent/synergistic drug combinations. Cell-death types (apoptosis, necrosis, autophagy, lysosomal death) and mechanisms (LMP, ATP depletion, oxidative stress, mitochondrial depolarization, signaling changes) will be defined by flow cytometry, immunoblotting, and confocal/electron microscopy, and confirmed with genetic/pharmacologic inhibitors. The results of this project could form the basis for a new therapeutic strategy for melanoma.
Donation of the organization "Climbers Against Cancer".