Dark Sweet Cherry Phenolics Enriched in Anthocyanins Suppressed Breast Cancer Lung Metastasis, Inhibited Tumor Growth, and Enhanced Doxorubicin Anticancer Activity In Vivo

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Objectives: To evaluate the effects of phenolics enriched in anthocyanins (ACN), doxorubicin (DOX) and their combination (COMB) in breast cancer progression and metastasis in 4T1 BALB/c mouse syngeneic model. Methods: 4T1 breast cancer cells were implanted into mammary fat pads of BALB/c mice which were separated by treatments. Control (CTRL) group was administered saline solution by gavage every other day. ACN group was treated with 150mg of ACN (quantified by the most abundant Cyanidin-3-O-Rutinoside) (C3R)/kg Body Weight (BW) by gavage every other day. DOX group received the drug (2mg/kg BW) by I.P. injection every 4 days, and COMB received both ACN and DOX at the same dose and time as individual treatments. Tumor volume, BW, and overall health were evaluated every other day up to 18-20 days (9-10 time points) after tumor volume reached 100mm3. Mice were euthanized when primary tumor reached 2000mm3 and/or mice showed signs of pain/distress. Tumors and main organs were collected, and lungs were stained with India ink to assess metastases rate (%) using ImageJ software. Results: At timepoint 9, tumor volume was lower in COMB compared to CTRL (p= 0.0006). Both ACN and COMB tumor volumes were similar and significantly lower than DOX (0.83- (p= 0.0217) and 0.78- (p=0.0007) fold of DOX, respectively). BW fold change from day 1 showed similarity between ACN and CTRL throughout the study. In contrast, DOX and COMB BW fold change was significantly lower than ACN after timepoint 6. Results from lung metastasis rate (% of tissue area with tumors) showed: DOX (33.19%±11%) ̴ CTRL (29.93%±7%) ̴ COMB (28.04%±9%) ̴) > CAN ( (18.23±9%) (p< 0.006). Conclusions: This study demonstrated that ACN slowed down the tumor growth and lung metastasis in an animal model resembling stage IV human breast cancer, characterized by poor prognosis and survival rate due to the cancer spread to the body. ACN treatment was also effective in enhancing the tumor growth inhibitory activity of DOX in COMB group. The benefits of ACN were accompanied by lack of side effects as found for DOX and COMB negative impact in BW. Overall, this study has shown the potential of ACN from DSC as a therapeutic agent in breast cancer chemoprevention in vivo. Funding Sources: Northwest Cherry Growers, Washington State Fruit Commission.