3D-Printed Culture Platform for Comparative Evaluation of the Cytotoxic and Molecular Effects of 3′,7-Dihydroxy-3′,4,5-Trimethoxyflavanone and 4,7- Didehydroneophysalin B in Breast Cancer

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Introduction: Natural compounds are rich sources of bioactive agents that can inhibit tumor growth and invasion during breast cancer progression. Many current breast cancer therapeutics are derived from natural products, including alkaloids, steroids, phenolic compounds, and flavonoids, which suppress angiogenesis, cell migration, and proliferation while modulating apoptosis- and cell cycle-related pathways. In this context, the present study investigated two naturally derived compounds, the flavonoid 3′,7-dihydroxy-3′,4,5- trimethoxyflavanone (FL) and the physalin derivative 4,7-didehydroneophysalin B (PB), for their effects on cisplatin- sensitive and cisplatin-resistant MDA-MB-231, a human triple-negative breast adenocarcinoma cell line derived from pleural effusion, under two-dimensional (2D) and three-dimensional (3D) conditions. Methods: Cisplatin-sensitive and cisplatin-resistant MDA-MB-231 breast cancer cells were cultured under 2D and 3D conditions and treated with FL and PB individually and in combination. Cell viability was assessed using XTT assays, migration capacity was evaluated using wound-healing assays, morphological alterations were examined microscopically, and the expression of apoptosis-associated genes and proteins was analyzed by qRTPCR and Western blotting. Molecular docking analysis was performed as a supporting in silico approach to evaluate the potential interactions between FL and PB and selected apoptosis-associated target proteins. Results: FL and PB exhibited cytotoxic and anti-migratory effects in both cisplatin-resistant and cisplatinsensitive cells, significantly reducing proliferation and migration. Combined treatment enhanced these effects, reduced proliferative capacity, and induced morphological changes. Gene and protein expression analyses demonstrated modulation of several apoptosis-associated markers, particularly following combined treatment. Molecular docking analysis indicated that FL and PB possess favorable predicted binding affinities toward the selected target proteins, supporting their potential as bioactive compounds for future biological investigations. Discussion: The enhanced efficacy observed following combined FL and PB treatment suggests a potential synergistic interaction, while differences between 2D and 3D models highlight the influence of tumor architecture on treatment response. Conclusions: These findings indicate that FL and PB exert promising anti-cancer effects in triple-negative breast cancer models and support further investigation of these compounds as potential therapeutic candidates, particularly in the context of chemoresistance.

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