考虑到乳腺癌（BC）对治疗的不良反应，我们评估了橙皮苷（hesperidin）对携带4T1 BC肿瘤的小鼠的治疗潜力。通过测量病理完全反应（pCR），生存分析，E-钙粘蛋白，VEGF，MMP9，MMP2和Ki-67的免疫组织化学染色，IFNγ和IL-4的血清测量，以及CD105，VEGFa，VEGFR2和COX2的基因表达分析评估了抗肿瘤效应。与正常生理盐水组（43％）相比，接受橙皮苷和多柔比星（Dox）联合治疗的小鼠的存活率最高（80％）。橙皮苷剂量为5mg/kg（54％），10mg/kg（55.5％），10mg/kg（60.5％）和40mg/kg（66％）的小鼠以及接受10mg/kg Dox治疗（73％）的小鼠的存活率均较正常生理盐水组高（p < 0.0001）。与正常生理盐水组相比，接受20mg/kg（p = 0.0026）和40mg/kg（p < 0.001）橙皮苷、10mg/kg Dox（p < 0.001）以及联合橙皮苷（20mg/kg）和Dox（10mg/kg）（p < 0.001）的动物的IFNγ水平显著升高。与仅接受10mg/kg Dox的小鼠相比，接受10mg/kg Dox + 20mg/kg橙皮苷治疗的小鼠的CD 105 (p = 0.0106)，VEGFa (p < 0.0001)，VEGFR2 (p < 0.0001)和Cox2 (p = 0.034)的基因表达显著降低，且病理完全反应（pCR）评分显著更高（p = 0.006）。免疫组织化学染色显示，与仅接受10mg/kg Dox的小鼠相比，接受10mg/kg Dox + 20mg/kg橙皮苷治疗的小鼠的Ki-67 (p < 0.001)，VEGF (p < 0.001) 显著减少，E-钙粘蛋白 (p = 0.005) 显著增加。橙皮苷可被视为一种潜在的适用于BC的抗癌药物，可与其他化疗药物产生协同效应。© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour effects were assessed by measuring pathologic complete response (pCR), survival analysis, immunohistochemistry for E-cadherin, VEGF, MMP9, MMP2 and Ki-67, serum measurement of IFNγ and IL-4, and gene expression analysis of CD105, VEGFa, VEGFR2 and COX2. Survival of tumour-bearing mice was the highest in mice receiving a combination of hesperidin and doxorubicin (Dox) (80%) compared to the normal saline (43%), hesperidin 5 (54%), 10 (55.5%), 10 (60.5%) and 40 (66%) mg/kg, and 10 mg/kg Dox-treated (73%) groups (p < 0.0001 for all). Compared to the normal saline group, there was a significant elevation in IFNγ level in the animals receiving 20 (p = 0.0026) and 40 (p < 0.001) mg/kg hesperidin, 10 mg/kg Dox (p < 0.001), and combined hesperidin (20 mg/kg) and Dox (10 mg/kg) (p < 0.001). A significant reduction in the gene expression of CD 105 (p = 0.0106), VEGFa (p < 0.0001), VEGFR2 (p < 0.0001), and Cox2 (p = 0.034) and a significant higher pCR score (p = 0.006) were noticed in mice treated with 10 mg/kg Dox + 20 mg/kg hesperidin compared to those treated with 10 mg/kg Dox alone. Immunohistochemical staining showed significant reductions in Ki-67 (p < 0.001) and VEGF (p < 0.001) and a significant elevation in E-cadherin (p = 0.005) in the 10 mg/kg Dox + 20 mg/kg treatment group than in 10 mg/kg Dox alone group. Hesperidin can be considered as a potentially suitable anti-cancer agent for BC that can synergize with other chemotherapeutics.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.