VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference
Stefano Conti Nibali,
Silvia De Siervi,
Enrico Luchinat,
Andrea Magrì,
Angela Messina,
Lorenza Brocca,
Stefania Mantovani,
Barbara Oliviero,
Mario U. Mondelli,
Vito De Pinto,
Cristian Turato,
Cristina Arrigoni,
Marco Lolicato
Affiliations
Stefano Conti Nibali
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Silvia De Siervi
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Enrico Luchinat
Department of Chemistry “Ugo Schiff”, University of Florence, via della Lastruccia 3, 50019 Firenze, Italy; Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine – CIRMMP, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
Andrea Magrì
Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
Angela Messina
Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
Lorenza Brocca
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Stefania Mantovani
Research Department, Division of Clinical Immunology—Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Barbara Oliviero
Research Department, Division of Clinical Immunology—Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Mario U. Mondelli
Research Department, Division of Clinical Immunology—Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
Vito De Pinto
Department of Biomedical and Biotechnological Sciences, Section of Biology & Genetics, University of Catania, Catania, Italy
Cristian Turato
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Cristina Arrigoni
Department of Molecular Medicine, University of Pavia, Pavia, Italy; Corresponding author
Marco Lolicato
Department of Molecular Medicine, University of Pavia, Pavia, Italy; Corresponding author
Summary: The voltage-dependent anion-selective channel isoform 1 (VDAC1) is a pivotal component in cellular metabolism and apoptosis with a prominent role in many cancer types, offering a unique therapeutic intervention point. Through an in-silico-to-in-vitro approach we identified a set of VA molecules (VDAC Antagonists) that selectively bind to VDAC1 and display specificity toward cancer cells. Biochemical characterization showed that VA molecules can directly interact with VDAC1 with micromolar affinity by competing with the endogenous ligand NADH for a partially shared binding site. NADH displacement results in mitochondrial distress and reduced cell proliferation, especially when compared to non-cancerous cells. Experiments performed on organoids derived from intrahepatic cholangiocarcinoma patients demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules with lower impact on healthy cells than conventional treatments like gemcitabine. VA molecules are chemical entities representing promising candidates for further optimization and development as cancer therapy strategies through precise metabolic interventions.
