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<p>Breast cancer remains a significant health concern for women worldwide. Here, we investigate the potential therapeutic role of the biphenyl dimeric compound 3,3’,5,5’-tetramethoxybiphenyl-4,4’-diol (TMBP), enzymatically synthesized from 2,6-dimethoxyphenol through an enzyme-catalyzed oxidation reaction. TMBP has shown the ability to diminish viability across various cancer cell lines by modulating oxidative and metabolic pathways, ultimately inducing cell death. We investigated the antiproliferative effects of TMBP in the MCF-7 breast cancer cell line and in 3D tumor spheroids. Cells were exposed to TMBP treatment, followed by comprehensive assessments of viability, migration, morphology, oxidative and metabolic stress markers, and cell death. Our findings reveal that TMBP treatment results in reduced viability, accompanied by morphological alterations including structural disruptions pertinent to cell migration, as well as the induction of autophagy-related morphological changes, lipid droplets, and disruption of mitochondrial membrane potential. TMBP triggered a pronounced oxidative imbalance, evidenced by increased ROS and NO production, elevated malondialdehyde (MDA) indicating lipid peroxidation, heightened catalase and superoxide dismutase activities, and a concomitant decrease in total glutathione. TMBP disrupted redox-mitochondrial homeostasis and compromised detoxification capacity. In the 3D tumor spheroids model, TMBP markedly decreased volume and viability, disrupted mitochondrial potential, and expanded the necrotic core relative to untreated controls. Altogether, these findings indicate that TMBP as a promising therapeutic agent capable of inhibiting tumor growth and inducing cell death in breast cancer models, supporting its potential development as a future treatment strategy.</p>

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The biphenyl dimeric compound 3,3’,5,5’-tetramethoxybiphenyl-4,4’-diol disrupts redox homeostasis and mitochondrial function to inhibit growth and induce apoptosis in breast cancer monolayers and 3D tumor spheroids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Virginia Marcia Concato-Lopes,
  • Ellen Mayara Souza Cruz,
  • Luan Vitor Alves de Lima,
  • Manoela Daiele Gonçalves-Lens,
  • Mariana Barbosa Detoni,
  • Milena Cremer de Souza,
  • Fernanda Tomiotto-Pellissier,
  • Amanda Cristina Machado Carloto,
  • Taylon Felipe Silva,
  • Bruna Taciane da Silva Bortoleti,
  • Fabricio Seidy Ribeiro Inoue,
  • Ana Carolina Jacob Rodrigues,
  • Jéseka Gabriela Schirmann,
  • Aneli M. Barbosa-Dekker,
  • Danielle Lazarin-Bidóia,
  • Robert F. H. Dekker,
  • Fabio Rodrigues Ferreira Seiva,
  • Mário Sérgio Mantovani,
  • Wander R. Pavanelli

摘要

Breast cancer remains a significant health concern for women worldwide. Here, we investigate the potential therapeutic role of the biphenyl dimeric compound 3,3’,5,5’-tetramethoxybiphenyl-4,4’-diol (TMBP), enzymatically synthesized from 2,6-dimethoxyphenol through an enzyme-catalyzed oxidation reaction. TMBP has shown the ability to diminish viability across various cancer cell lines by modulating oxidative and metabolic pathways, ultimately inducing cell death. We investigated the antiproliferative effects of TMBP in the MCF-7 breast cancer cell line and in 3D tumor spheroids. Cells were exposed to TMBP treatment, followed by comprehensive assessments of viability, migration, morphology, oxidative and metabolic stress markers, and cell death. Our findings reveal that TMBP treatment results in reduced viability, accompanied by morphological alterations including structural disruptions pertinent to cell migration, as well as the induction of autophagy-related morphological changes, lipid droplets, and disruption of mitochondrial membrane potential. TMBP triggered a pronounced oxidative imbalance, evidenced by increased ROS and NO production, elevated malondialdehyde (MDA) indicating lipid peroxidation, heightened catalase and superoxide dismutase activities, and a concomitant decrease in total glutathione. TMBP disrupted redox-mitochondrial homeostasis and compromised detoxification capacity. In the 3D tumor spheroids model, TMBP markedly decreased volume and viability, disrupted mitochondrial potential, and expanded the necrotic core relative to untreated controls. Altogether, these findings indicate that TMBP as a promising therapeutic agent capable of inhibiting tumor growth and inducing cell death in breast cancer models, supporting its potential development as a future treatment strategy.