Work

7,8-Dihydroxyflavone enhances the chemosensitivity of hepatocellular carcinoma cells to arsenic trioxide by disrupting mitochondrial oxidative phosphorylation

Year: 2025

Type: article

Abstract: • The combination of ATO and DHF inhibited the progression of HCC cells. • Co-treatment with DHF and ATO inhibited mitochondrial function. • Co-treatment with DHF and ATO suppressed mitochondrial OXPHOS. • A low dose of CCCP reversed the effects of DHF and ATO co-treatment. Arsenic trioxide (ATO) has a well-documented history in traditional Chinese medicine as an effective treatment for acute promyelocytic leukemia and certain solid tumors; however, its efficacy as a standalone chemotherapy agent is limited. 7,8-Dihydroxyflavone (DHF), a TrkB receptor agonist, has shown promising anticancer effects across various malignancies. This study aimed to investigate the therapeutic potential of DHF, both alone and in combination with ATO, in hepatocellular carcinoma (HCC) cells. The HCCLM3 and HepG2 cell lines were treated with ATO and DHF, alone or in combination. Cell viability and death ratio were assessed using MTT and live/dead staining. Proliferation and migration were evaluated through EdU staining, wound-healing assays, and colony formation assays. Apoptosis was detected via TUNEL staining, while changes in morphology and mitochondrial function were assessed using Mito-Tracker, transmission electron microscopy, mito-SOX, and JC-1 staining. The combination of DHF and ATO significantly reduced cell viability, proliferation, and migration, while concurrently increasing cell death and apoptosis compared to monotherapy. Mechanistically, combination treatment notably decreased mitochondrial membrane potential, increased the production of mitochondrial reactive oxygen species (ROS), and suppressed mitochondrial respiration, which was accompanied by reduced protein levels of mitochondrial complexes I, II, III, and V. Furthermore, these effects were reversed by the mitochondrial uncoupler CCCP at a low dose. These findings suggest that the DHF-ATO combination suppresses HCC progression by impairing mitochondrial oxidative phosphorylation, providing a promising strategy to enhance chemotherapeutic efficacy.

Source: Pharmacological Research - Modern Chinese Medicine

DOI: 10.1016/j.prmcm.2025.100693