Trihydroxylated Anthocyanins Potentiate Effects of Docetaxel in Mesenchymal Triple Negative Breast Cancer Cells
Mafalda Ribeiro1,2,3, Miguel A Faria1, Martin Vojtek3
1LAQV/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Abstract:
Triple negative breast cancer (TNBC) presents a significant therapeutic challenge due to its poor prognosis and limited treatment options. While anthocyanins, a group of flavonoids, exhibit promising anticancer potential, their structure-activity relationship and adjuvant properties in TNBC remain underexplored. This study evaluated the anti-proliferative effects of five structurally distinct anthocyani(di)ns-cyanidin-3-O-glucoside (C3G), delphinidin-3-O-glucoside (D3G), delphinidin-3-O-rutinoside (D3R), malvidin-3-O-glucoside (M3G), and luteolinidin (LT)-on mesenchymal TNBC cells. Combination assays of docetaxel (DT), a first-line chemotherapeutic agent, with the most potent anthocyani(di)ns were conducted with TNBC and MCF-12A non-cancerous cells. Trihydroxylated anthocyanins (D3G and D3R), particularly those with a monosaccharide at C3, demonstrated the strongest anti-proliferative effects, reducing MDA-MB-231 cell proliferation by 95% and 70%, respectively, at 400 μM (IC50: 253.28 and 341.33 μM) without affecting MCF-12A cells. These were followed by 3-deoxy (LT), dihydroxylated (C3G), and O-methylated (M3G) anthocyani(di)ns. In Hs 578T mesenchymal TNBC cells, the trihydroxylated anthocyanins tested also induced strong anti-proliferative effects. Synergistic effects (combination index < 0.9) were observed for binary (D3G + DT or D3R + DT) and ternary (D3G + D3R + DT) combinations, reducing DT concentrations by up to 37-fold and anthocyanin concentrations by up to 21.9-fold to achieve similar inhibition. The ternary combination was the most effective, requiring the lowest concentrations of DT and anthocyanins. These results underscore the critical role of the ortho-trihydroxylated structure in the anti-proliferative effects of anthocyani(di)ns, highlighting trihydroxylated anthocyanins as promising adjuvants in TNBC treatment, with the potential to lower DT dosage, minimize side effects, delay resistance, and reduce treatment costs while maintaining efficacy.
Insights
Trihydroxylated anthocyanins show potent anti-proliferative effects against triple-negative breast cancer (TNBC) cells. These natural compounds, when combined with docetaxel, act synergistically, potentially reducing chemotherapy dosage and side effects.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Toxicology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) poses a significant therapeutic challenge due to limited treatment options and poor prognosis.
- Anthocyanins, a class of flavonoids, possess anticancer properties, but their specific role and structure-activity relationship in TNBC are not well understood.
- Exploring novel adjuvant therapies is crucial to improve TNBC treatment outcomes and mitigate the toxicity of conventional chemotherapy.
Purpose of the Study:
- To evaluate the anti-proliferative activity of five structurally diverse anthocyanins against mesenchymal TNBC cells.
- To investigate the synergistic effects of potent anthocyanins in combination with docetaxel (DT), a standard chemotherapeutic agent.
- To determine the structure-activity relationship of anthocyanins concerning their efficacy in TNBC treatment.
Main Methods:
- In vitro anti-proliferative assays were performed on TNBC cell lines (MDA-MB-231, Hs 578T) and non-cancerous MCF-12A cells using five anthocyanins: cyanidin-3-O-glucoside (C3G), delphinidin-3-O-glucoside (D3G), delphinidin-3-O-rutinoside (D3R), malvidin-3-O-glucoside (M3G), and luteolinidin (LT).
- Combination assays were conducted using the most effective anthocyanins (D3G, D3R) with docetaxel (DT) to assess synergistic effects via combination index (CI) calculations.
- Cell viability and proliferation inhibition were quantified to determine IC50 values and evaluate treatment efficacy.
Main Results:
- Trihydroxylated anthocyanins, specifically D3G and D3R, exhibited the strongest anti-proliferative effects on MDA-MB-231 cells, achieving up to 95% inhibition at 400 μM.
- The ortho-trihydroxylated structure was identified as critical for potent anti-proliferative activity, outperforming dihydroxylated, 3-deoxy, and O-methylated analogues.
- Synergistic effects (CI < 0.9) were observed in binary (D3G/D3R + DT) and ternary (D3G + D3R + DT) combinations, significantly reducing the required concentrations of both DT (up to 37-fold) and anthocyanins (up to 21.9-fold).
Conclusions:
- Trihydroxylated anthocyanins are potent anti-proliferative agents against TNBC cells and demonstrate significant synergistic activity with docetaxel.
- These findings highlight the potential of trihydroxylated anthocyanins as effective adjuvant therapies for TNBC, capable of enhancing treatment efficacy while reducing chemotherapy dosage.
- The use of anthocyanin adjuvants could lead to minimized side effects, delayed resistance, reduced treatment costs, and improved overall patient outcomes in TNBC management.
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