3,3’,5,5’-Tetramethoxybiphenyl-4,4’-diol exerts a cytotoxic effect on hepatocellular carcinoma cell lines by inducing morphological and ultrastructural alterations, G2/M cell cycle arrest and death by apoptosis via CDK1 interaction - 17/05/25
, Virginia Marcia Concato-Lopes a, Bruna Taciane da Silva Bortoleti a, Ellen Mayara Souza Cruz a, Mariana Barbosa Detoni a, Fernanda Tomiotto-Pellissier a, b, Manoela Daiele Gonçalves-Lens c, Juliana Maria Bitencourt de Morais-Valentim a, Rayanne Regina Beltrame Machado d, Kaio Maciel Santiago-Silva e, Marcelle de Lima Ferreira Bispo e, Jéseka Gabriela Schirmann f, Aneli M. Barbosa-Dekker f, g, Robert F.H. Dekker g, Maria Claudia Terkelli de Assis h, Ivete Conchon-Costa a, Mário Sérgio Mantovani h, Danielle Lazarin-Bidóia a, d, Carolina Panis i, Wander Rogério Pavanelli aAbstract |
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with frequent recurrence and chemoresistance, underscoring the need for new treatment strategies. 3,3’,5,5’-Tetramethoxybiphenyl-4,4’-diol (TMBP) showed cytotoxicity against lung cancer cell lines without harming normal cells. Thus, we investigated the antitumoral effect of TMBP on HCC cell lines, HuH7.5 (p53-mutant) and HepG2/C3A (p53-wild type). Cells were treated with TMBP (12.5–150 µM) for 24 and 48 h, and metabolic cellular activity (MTT) were used to determine the 50 % inhibitory concentration (IC50) values. TMBP cytotoxicity were assessed by Trypan blue assay, scanning and transmission electron microscopy. Cell migration (wound healing), total ROS (H2DCFDA), mitochondrial dysfunction (TMRE), lipid droplets (Nile Red), and autophagic vacuoles (MDC) were assessed. Flow cytometry characterized cell cycle distribution and cell death. Caspase 3/7 activity and CASP3 expression confirmed apoptosis. Molecular docking and gene expression analysis validated TMBP-CDK1 interaction. TMBP reduced cell viability, with IC50 values of 68 and 55 µM (HuH7.5) and 50 and 42 µM (HepG2/C3A) at 24 and 48 h. TMBP induced severe morphological alterations, impaired migration, increased ROS, mitochondrial dysfunction, increased lipid droplets and autophagic vacuoles. TMBP also led to G2/M arrest and apoptosis, likely via CDK1 inhibition through hydrogen bonding at Tyr15. These findings highlight TMBP as a promising therapeutic candidate targeting CDK1 in HCC.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | TMBP promotes severe morphological alterations and impaired migration in HCC cells. |
• | TMBP-treated HCC cells present increased ROS/NOx levels along with loss of ∆Ψm. |
• | TMBP-induced stress led to increased lipid droplets and autophagic vacuoles. |
• | TMBP induces G2/M cell cycle arrest and apoptosis in HCC-treated cells. |
• | TMBP inhibits CDK1 protein activation via hydrogen bond with Tyr15 residue. |
Keywords : Biphenyl compound, Antiproliferation, Reactive oxygen species, Mitochondrial dysfunction, Caspase 3/7
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Vol 187
Article 118082- juin 2025 Retour au numéro
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