Nava-Ochoa Ana, Stranahan Lauren W, San-Cristobal Rodrigo, Mertens-Talcott Susanne U, Noratto Giuliana D
Department of Food Science and Technology, Texas A & M University, College Station, TX 77843, USA.
Department of Veterinary Pathobiology, School of Veterinary Medicine & Biomedical Sciences, Texas A & M University, College Station, TX 77843, USA.
Int J Mol Sci. 2025 Jul 25;26(15):7225. doi: 10.3390/ijms26157225.
Dark sweet cherries (DSC) phytochemicals have emerged as a promising dietary strategy to combat triple-negative breast cancer (TNBC). This study explored the effects of DSC extract rich in anthocyanins (ACN) as a chemopreventive agent and as a complement to doxorubicin (DOX) in treating TNBC tumors and metastasis using a 4T1 syngeneic animal model. Initiating ACN intake as a chemopreventive one week before 4T1 cell implantation significantly delayed tumor growth without any signs of toxicity. Both DOX treatment and the combination of DOX-ACN effectively delayed tumor growth rate, but DOX-ACN allowed for body weight gain, which was hindered by DOX alone. As a chemopreventive, ACN downregulated metastasis- and immune-suppression-related genes, including STAT3, Snail1, mTOR, SIRT1, TGFβ1, IKKβ, and those unaffected by DOX alone, such as HIF, Cd44, and Rgcc32. Correlations between mRNA levels seen in control and DOX groups were absent in ACN and/or DOX-ACN groups, indicating that Cd44, mTOR, Rgcc32, SIRT1, Snail1, and TGFβ1 may be ACN targets. The DOX-ACN treatment showed a trend toward enhanced efficacy involving CREB, PI3K, Akt-1, and Vim compared to DOX alone. Particularly, ACN significantly suppressed lung metastasis compared to the other groups. ACN also decreased the frequency and incidence of metastasis in the liver, heart, kidneys, and spleen, while their metastatic area (%) and number of breast cancer (BC) metastatic tumor nodules were lowered without reaching significance. Further research is needed to explore the efficacy of combining ACN with drug therapy in the context of drug resistance.
黑甜樱桃（DSC）的植物化学物质已成为对抗三阴性乳腺癌（TNBC）的一种有前景的饮食策略。本研究使用4T1同基因动物模型，探讨了富含花青素（ACN）的DSC提取物作为化学预防剂以及作为阿霉素（DOX）治疗TNBC肿瘤和转移的补充剂的效果。在植入4T1细胞前一周开始摄入ACN作为化学预防剂，可显著延迟肿瘤生长，且无任何毒性迹象。DOX治疗以及DOX-ACN联合治疗均有效延迟了肿瘤生长速度，但DOX-ACN能使体重增加，而单独使用DOX则会阻碍体重增加。作为化学预防剂，ACN下调了与转移和免疫抑制相关的基因，包括STAT3、Snail1、mTOR、SIRT1、TGFβ1、IKKβ，以及那些单独使用DOX时不受影响的基因，如HIF、Cd44和Rgcc32。在ACN和/或DOX-ACN组中未发现对照组和DOX组中观察到的mRNA水平之间的相关性，这表明Cd44、mTOR、Rgcc32、SIRT1、Snail1和TGFβ1可能是ACN的靶点。与单独使用DOX相比，DOX-ACN治疗在涉及CREB、PI3K、Akt-1和Vim方面显示出疗效增强的趋势。特别是，与其他组相比，ACN显著抑制了肺转移。ACN还降低了肝脏、心脏、肾脏和脾脏转移的频率和发生率，同时其转移面积（%）和乳腺癌（BC）转移瘤结节数量有所降低，但未达到显著水平。需要进一步研究探索在耐药情况下将ACN与药物治疗联合使用的疗效。
