Therapy-resistant breast cancer in focus: Clinically relevant mitigation by flavonoids targeting cancer stem cells

Abstract

Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.

A study with cancer stem cells and three-dimensional tumoroids: investigation of the combined effects of 5-fluorouracil and doxorubicin in breast cancer

“…This result is consistent with the scientific article published by Gong et al in 2015[ 9 ]. In addition, when 2D and 3D culture conditions were evaluated together, it was determined that breast cancer stem cells were more resistant than the MCF-7 cancer cell line and required higher drug doses and longer incubation periods to observe a significant antiproliferative effect [ 24 , 25 ]. This result also shows high compatibility with the relevant literature [ 4 , 6 , 23 , 24 ].…”

“…In addition, when 2D and 3D culture conditions were evaluated together, it was determined that breast cancer stem cells were more resistant than the MCF-7 cancer cell line and required higher drug doses and longer incubation periods to observe a significant antiproliferative effect [ 24 , 25 ]. This result also shows high compatibility with the relevant literature [ 4 , 6 , 23 , 24 ]. In this study designed with MCF-7, a HER2-negative breast cancer cell line, the observation of a synergistic effect for 5-Fu and Dox is of extra importance, together with the data presented in another study published by Mody et al in 2023.…”

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling

“…On the other hand, specific plant-derived molecules or plant extracts have been described to overcome multidrug resistance (MDR) in BC, including flavonoids [ 18 – 20 ]. The simultaneous treatment of standard anti-BC drugs and plant-derived substances represents a rational clinical approach to avoid the potential loss of effectiveness using conventional chemotherapeutic agents alone [ 21 ].…”

“…Flavonoids, of which over 8000 molecules are known, are abundant in plants, foods, and herbs. As multi-target components, flavonoids show several beneficial activities, such as anti-inflammatory and anti-cancer [ 18 , 21 – 35 ], as well as modulate the plasticity of cancer cells with the ability to reverse tumor resistance to chemotherapeutic agents while exhibiting very low toxicity and very high efficacy [ 36 ]. They possess a broad spectrum of anticancer activities, including suppressing NF-κB triggered signaling [ 18 ].…”