2025/10/31 by Mücahit Varlı, Young Hyun Yu, Jieun Yu +5 · 1 voice
Agricultural and Biological Sciences · Biochemistry, Genetics and Molecular Biology · Medicine · #Biotin and Related Studies #Fungal Biology and Applications #Lichen and fungal ecology
paper · pdf · doi:10.1002/mco2.70446
openalex publication_date 2025/10/31 · openalex created_date 2025/11/01 · openalex updated_date 2026/06/14
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 colorectal adenocarcinoma-enriched stem cells. In vivo, SB4 and SB5 displayed higher tumor, liver, and intestinal bioavailability than TU and DA following intraperitoneal administration. Pharmacokinetic analyses indicated SB4 had a comparable absorption profile to SB5 with distinct systemic exposures differences. In a CT26/near-infrared fluorescent protein tumor model, SB4 markedly inhibited tumor growth and modulated key markers of stemness, motility, metabolism, and apoptosis in tumor tissues. Collectively, these findings demonstrate that SB4 and SB5 are promising candidates for colorectal cancer therapy by targeting VDAC1/PHB/MMP9.