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Updated: Jun 25, 2025
Author Spotlight: Understanding Cytokine-Induced Cell Death in Intestinal Epithelial Cells Using Human Organoids
Published on: August 2, 2024
VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic
Stefano Conti Nibali1, Silvia De Siervi1, Enrico Luchinat2,3
1Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Abstract:
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.
Insights
New VDAC antagonist molecules selectively target cancer cells by disrupting mitochondrial function. These VDAC antagonists show promise for cancer therapy with reduced impact on healthy cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Voltage-dependent anion-selective channel isoform 1 (VDAC1) is crucial in cellular metabolism and apoptosis.
- VDAC1 plays a significant role in various cancer types, presenting a therapeutic target.
Purpose of the Study:
- To identify novel molecules that selectively target VDAC1 in cancer cells.
- To investigate the mechanism of action and therapeutic potential of these VDAC antagonists.
Main Methods:
- In silico screening followed by in vitro validation.
- Biochemical assays to characterize VDAC1-VA molecule interactions.
- Cell proliferation and viability assays on cancer cell lines and patient-derived organoids.
Main Results:
- Identified VDAC antagonists (VA molecules) that bind to VDAC1 with micromolar affinity.
- VA molecules compete with NADH, causing mitochondrial distress and reduced cancer cell proliferation.
- Demonstrated dose-dependent reduction in intrahepatic cholangiocarcinoma cell viability with minimal impact on healthy cells.
Conclusions:
- VA molecules selectively target cancer cells by inhibiting VDAC1.
- These compounds represent promising candidates for developing targeted cancer therapies.
- Targeting VDAC1 offers a precise metabolic intervention strategy for cancer treatment.
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