Three-dimensional cell cultures as preclinical models to assess the biological activity of phytochemicals in breast cancer

The demand for the development of three-dimensional (3D) cell culture models in both/either drug screening and/or toxicology is gradually magnified. Natural Products derived from plants are known as phytochemicals and serve as resources for novel drugs and cancer therapy. Typical examples include taxol analogs (i.e., paclitaxel and docetaxel), vinca alkaloids (i.e., vincristine, vinblastine), and camptothecin analogs (topotecan, irinotecan). Breast cancer is the most frequent malignancy in women, with a 70% chance of patients being cured; however, metastatic disease is not considered curable using currently available chemotherapeutic options. In addition, phytochemicals present promising options for overcoming chemotherapy-related problems, such as drug resis-tance and toxic effects on non-target tissues. In the toxicological evaluation of these natural compounds, 3D cell culture models are a powerful tool for studying their effects on different tissues and organs in similar environ-ments and behave as if they are in vivo conditions. Considering that 3D cell cultures represent a valuable platform for identifying the biological features of tumor cells as well as for screening natural products with antitumoral activity, the present review aims to summarize the most common 3D cell culture methods, focusing on multi -cellular tumor spheroids (MCTS) of breast cancer cell lines used in the discovery of phytochemicals with anti-cancer properties in the last ten years.