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Breast cancer (BC) remains the second most common cause of cancer-related deaths in women in the US, despite advances in detection and treatment. In addition, breast cancer survivors often struggle with long-term treatment related comorbidities. Identifying novel therapies that are effective while minimizing toxicity is critical in curtailing this disease. Flavonoids, a subclass of plant polyphenols, are emerging as promising treatment options for the prevention and treatment of breast cancer. Recent evidence suggests that in addition to anti-oxidant properties, flavonoids can directly interact with proteins, making them ideal small molecules for the modulation of enzymes, transcription factors and cell surface receptors. Of particular interest is the ability of flavonoids to modulate the tumor associated macrophage function. However, clinical applications of flavonoids in cancer trials are limited. Epidemiological and smaller clinical studies have been largely hypothesis generating. Future research should aim at addressing known challenges with a broader use of preclinical models and investigating enhanced dose-delivery systems that can overcome limited bioavailability of dietary flavonoids.
Study Type | Experimental Model | Treatments | Dose | Results | Reference |
---|---|---|---|---|---|
Cellular Studies | T47D and MCF-7 | Wine polyphenols | 1 pM–100 nM | Inhibited growth and antagonize H2O2 | [17] |
HCC70, BT-474 and T47D | Butein | 0.001–100 μg/mL | Induced apoptosis through ROS reduction | [19] | |
MDA-MB-468 | Naringenin | 2.5–50 μM | Oxidative stress induced apoptosis | [20] | |
MDA-MB-231 and MDA-MB-468 | Myricetin | 20–100 μM | Oxidative stress induced apoptosis | [21] | |
MDA-MB-453 | 5,7-dihydroxy, 8-nitrochrysin | 2–8 μM | Induced apoptosis by generation of ROS | [24] | |
MDA-MB-231 | Silibinin | 30 μM | Induced apoptosis | [25] | |
Human monocytes and RAW 264.7 | Apigenin | 0.1–25 μM | Reduced NFκB phosphorylation, TNF-α and IL-1β expression | [13] | |
RAW 264.7 | Chrysin | 30 μM | Suppression IL-1β expression | [43] | |
RAW 264.7 | Apigenin | 10–25 μM | Reduced NOS and COX expression | [44] | |
ANA-1 | Apigenin | 12.5–200 μM | Induced apoptosis | [45] | |
Human PBMC | Quercetin | 1–50 μM | Inhibited TNF-α expression | [48] | |
Human Neutrophils | Hesperidin | 1–100 μM | Reduced ROS generation and induced apoptosis | [51] | |
Human Dendritic cells | EGCG | 10–100 μM | Induced apoptosis | [53] | |
RAW 264.7 | Luteolin | 25–100 μM | Inhibited COX-2 and xanthine oxidase expression | [54] | |
Bone marrow derived mouse macrophages | Quercetin and Kaempferol | 25–50 μM | Inhibited TNF-α expression | [56] | |
MCF-7 | Apigenin and Chrysin | 10–50 μM | BCRP inhibitors | [57] | |
MCF-7 and T47D | Methoxyflavones from Tanacetum gracile | 1.5–5 μM | Induced cell cycle arrest through tubulin binding | [58] | |
MDA-MB-231 | Apigenin | 25 μM | Inhibited hnRNPA2 dimerization affecting its splicing activity | [59] | |
MCF-7 | Apigenin | 25–100 μM | Suppressed MUC-1 expression and induced apoptosis | [60] | |
Cellular Study | CD4 T cells | Apigenin | 12.5–75 μM | Potentiated activation induced cell death by suppressing NFκB regulated anti-apoptotic pathways | [61] |
Dendritic cells | Quercetin | 50 μM | Attenuated LPS induced DC activation | [62] | |
MCF-7 | Apigenin | 20–80 μM | Reduced cell growth and expression of MDR1 and P-gp in MCF-7-doxorubicin resistant cells | [63] | |
MCF-7, MDA-MB-231 and HMF | Rutin | 20 μM | Increased the cytotoxicity of cyclophosphamide and methotrexate | [64] | |
MDA-MB-231 | EGCG | 10–25 μM | Synergistic enhancement of cytotoxicity with tamoxifen | [65] | |
MCF-7 | Resveratrol | 50–250 μM | Increased sensitivity to doxorubicin | [40] | |
MDA-MB-231 and MCF-7 | Resveratrol | 80–180 μM | Synergistic inhibition of growth with doxorubicin | [66] | |
MCF-7 | Apigenin | 30 μM | Enhanced cisplatin cytotoxic activity | [67] | |
BT-474 and SK-BR3 | Flavopiridol | 50–100 nM | Synergistic inhibition of cell proliferation with trastuzumab | [68] | |
MDA-MB-231, MDA-MB-468 and SK-BR3 | Flavopiridol | 0.2 μM | Enhanced sorafenib induced cytotoxicity | [69] | |
BT47D and MDA-MB-231 | Apigenin | 10–80 μM | Induced apoptosis and autophagy | [70] | |
MDA-MB-231 | Wogonin | 50–100 μM | Sensitized TRAIL-induced apoptosis | [71] | |
RAW 264.7 macrophages and 3T3-L1 adipocytes co-culture | Luteolin | 1–20 μM | Suppressed the adipocyte-dependent activation ofmacrophage | [72] | |
3D Study | MDA-MB-231 | Apigenin and Luteolin | 20 μM | Attenuate growth and intravasation through endothelial barrier | [30] |
Animal Study | BALB/C-Tg (NFκB-RE-luc)-Xen mice | Apigenin | 50 mg/kg body weight | Reduced NFκB activity in lungs in vivo | [46] |
CD-1 immunodeficient mice bearing MDA-MB-231 tumor | Oncamex | 25 mg/kg body weight | Inhibited tumor growth | [28] | |
Athymic nu/nu nude mice bearing MDA-MB-231 tumors | Radix Glycyrrhiza extracts | 20–100 mg/kg body weight | Attenuated tumor growth through iNOS inhibition | [29] | |
C57BL/6 mice | Luteolin | HFD with 0.01% luteolin | Inhibited inflammatory macrophage polarization in adipose tissue | [73] | |
C57BL/6 mice | Quercetin | HFD with 0.1% luteolin | Attenuated macrophage recruitment and modulated M1/M2 macrophage ratio | [74] | |
BALB/c mice bearing 4T1 tumors | Quercetin | 5mg/kg body weight | Synergistic inhibition of tumor growth with doxorubicin | [75] | |
Athymic nu/nu nude mice bearing BT47D tumors | Apigenin | 50 mg/kg body weight | Inhibited the progression progestin dependent BT-474 xenograft tumors in nude mice through apoptosis | [76] | |
Athymic nu/nu nude mice bearing MDA-MB-231 tumors | Apigenin | 25–50 mg/kg body weight | Inhibited tumor proliferation and proteasome activity | [77] | |
Ovariectomized C57BL/6 mice injected with E0771 cells | Naringenin | HFD with 1–3% naringenin | Reduced adipose tissue mass and ameliorated adipose tissue inflammation | [78] | |
C57BL/6 mice | Hippophae rhamnoides L. seeds extracts | 100–300 mg/kg body weight | Significant anti-obesity and anti-inflammatory effect | [79] | |
Ovariectomized female C57BL/6 mice | Resveratrol | 300–600 mg/kg body weight | Inhibited obesity-associated increases in claudin-low mammary tumor growth and macrophage infiltration | [80] |