Synthesized Depside Molecules Suppress the Progression of Colorectal Cancer by Binding VDAC1/PHB/MMP9 Being at the Crossroads of Stemness, Motility, Apoptosis, and Metabolism.

ABSTRACT: Lichen secondary metabolites have shown potential in cancer therapy, but strategies to enhance cancer-specific selectivity are needed. Here, we synthesized depside compounds structurally related to tumidulin (TU) and diffractaic acid (DA) and screened them in vitro, identifying SB4 and SB5 as potent hits. Affinity-based proteomics revealed direct binding to voltage-dependent anion channel 1 (VDAC1), prohibitin (PHB), and matrix metalloproteinase-9 (MMP9), which regulate cancer stemness, motility, metabolism, and apoptosis. SB4 and SB5 exhibited strong cytotoxicity, suppressed cancer stem cell characteristics, inhibited cell motility, impaired mitochondrial respiration, induced reactive oxygen species, and promoted apoptosis. Notably, they reversed cetuximab-induced cancer stemness in color

SUBMITTER: Varlı M 

PROVIDER: S-EPMC12579162 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature