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
8 affiliations
- 1Department of Immunology, Parasitology and General Pathology, Laboratory of Immunoparasitology of Neglected Diseases and Cancer, State University of Londrina, Post Box 10.011, Londrina, PR 86057-970 Brazil
- 2Department of General Biology, Laboratory of Toxicological Genetics, State University of Londrina, Londrina, PR Brazil
- 3Department of Chemistry, Laboratory of Biotransformation and Phytochemical, State University of Londrina, Londrina, PR Brazil
- 4Department of Chemistry and Biochemistry, UNESP, São Paulo State University, Institute of Biosciences, Botucatu, São Paulo, 18618-689 Brazil
- 5Department of Medical Pathology, Federal University of Paraná, Curitiba, PR Brazil
- 6Graduate Program in Biosciences and Biotechnology, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, PR Brazil
- 7Department of Chemistry, Laboratory Research of Bioactive Molecules, State University of Londrina, Londrina, PR Brazil
- 8Beta-Glucan Produtos Farmoquímicos-EIRELI, Lote 24A - Bloco Zirconia, Universidade Tecnológica Federal do Paraná, Avenida João Miguel Caram 731, Londrina, Paraná 86036-700 Brazil
Abstract
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16610-1.
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BibTeX
@article{concatolopes2026biphenyl,
title = {{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}},
author = {Virginia Marcia Concato-Lopes and Ellen Mayara Souza Cruz and Luan Vitor Alves de Lima and Manoela Daiele Gonçalves-Lens and Mariana Barbosa Detoni and Milena Cremer de Souza and Fernanda Tomiotto-Pellissier and Amanda Cristina Machado Carloto and Taylon Felipe Silva and Bruna Taciane da Silva Bortoleti and Fabricio Seidy Ribeiro Inoue and Ana Carolina Jacob Rodrigues and Jéseka Gabriela Schirmann and Aneli M. Barbosa-Dekker and Danielle Lazarin-Bidóia and Robert F. H. Dekker and Fabio Rodrigues Ferreira Seiva and Mário Sérgio Mantovani and Wander R. Pavanelli},
journal = {BMC Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12885-026-16610-1},
url = {https://doi.org/10.1186/s12885-026-16610-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Virginia Marcia Concato-Lopes
AU - Ellen Mayara Souza Cruz
AU - Luan Vitor Alves de Lima
AU - Manoela Daiele Gonçalves-Lens
AU - Mariana Barbosa Detoni
AU - Milena Cremer de Souza
AU - Fernanda Tomiotto-Pellissier
AU - Amanda Cristina Machado Carloto
AU - Taylon Felipe Silva
AU - Bruna Taciane da Silva Bortoleti
AU - Fabricio Seidy Ribeiro Inoue
AU - Ana Carolina Jacob Rodrigues
AU - Jéseka Gabriela Schirmann
AU - Aneli M. Barbosa-Dekker
AU - Danielle Lazarin-Bidóia
AU - Robert F. H. Dekker
AU - Fabio Rodrigues Ferreira Seiva
AU - Mário Sérgio Mantovani
AU - Wander R. Pavanelli
PY - 2026
DA - 2026/07/30
JO - BMC Cancer
DO - 10.1186/s12885-026-16610-1
UR - https://doi.org/10.1186/s12885-026-16610-1
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16610-1.
SN - 1471-2407
ER -