Méndez Utz V E, Pérez Visñuk D, Perdigón G, de Moreno de LeBlanc A
Centro de Referencia para Lactobacilos (CERELA-CONICET), CP T4000ILC, San Miguel de Tucumán, Argentina.
Cátedra de Inmunología. Facultad de Bioquímica, Química y Farmacia. Universidad Nacional de Tucumán, San Miguel de Tucumán, Tucumán, Argentina.
Appl Microbiol Biotechnol. 2021 Jan;105(1):327-340. doi: 10.1007/s00253-020-11007-x. Epub 2020 Nov 18.
Chemotherapy is the most common treatment for breast cancer and its metastasis; however, it affects the patients' quality of life. Previously, it was demonstrated that milk fermented by Lactobacillus casei CRL431 (probiotic fermented milk (PFM)) exerted benefits against breast cancer metastasis by modulating the immune response in a mouse model. The aim of this work was to evaluate PFM administration on the side effects of capecitabine and on its anti-tumour/anti-metastatic effects. In vitro, 4T1 breast cancer cells were treated with capecitabine in the presence of immune cells' conditioned media from mice administered with PFM. Cell viability was evaluated by MTT assay. In vivo, BALB/c mice (healthy, bearing breast cancer or with potential metastasis) were treated or not with capecitabine and administered with PFM. Blood cell counts, intestinal damages, lung histology and serum cytokines were evaluated. Results showed that capecitabine's toxicity on 4T1 cells was improved by the immune cells from mice that received PFM when the lower dose of capecitabine was evaluated. PFM reduced capecitabine side effects in all the mouse models and decreased intestinal mucositis and mortality. PFM administration to mice under chemotherapy maintained the anti-cancer/anti-metastasis effect of capecitabine with similar or decreased values for serum IL-10 and TNF-α and decreased IL-6, a cytokine related to poor prognosis in advanced cancer patients. In addition, PFM by itself reduced metastasis without side effects and improved the host's immune response. PFM has a potential to be administered as an immune adjuvant in patients under chemotherapy without affecting the treatment. KEY POINTS: • Milk fermented by L. casei CRL431 (PFM) diminished capecitabine side effects. • Capecitabine's toxicity on 4T1 cells was improved by the PFM-stimulated immune cells. • PFM maintained anti-cancer/anti-metastasis effect of capecitabine in mouse models. Graphical abstract.
化疗是乳腺癌及其转移最常见的治疗方法；然而，它会影响患者的生活质量。此前，已证明干酪乳杆菌CRL431发酵的牛奶（益生菌发酵乳（PFM））通过调节小鼠模型中的免疫反应对乳腺癌转移具有益处。这项工作的目的是评估PFM给药对卡培他滨副作用及其抗肿瘤/抗转移作用的影响。在体外，在来自给予PFM的小鼠的免疫细胞条件培养基存在下，用卡培他滨处理4T1乳腺癌细胞。通过MTT法评估细胞活力。在体内，对BALB/c小鼠（健康、患有乳腺癌或有潜在转移）给予或不给予卡培他滨并给予PFM。评估血细胞计数、肠道损伤、肺组织学和血清细胞因子。结果表明，当评估较低剂量的卡培他滨时，接受PFM的小鼠的免疫细胞可改善卡培他滨对4T1细胞的毒性。PFM降低了所有小鼠模型中卡培他滨的副作用，并降低了肠道粘膜炎和死亡率。对化疗小鼠给予PFM可维持卡培他滨的抗癌/抗转移作用，血清IL-10和TNF-α的值相似或降低，而与晚期癌症患者预后不良相关的细胞因子IL-6降低。此外，PFM本身可减少转移且无副作用，并改善宿主的免疫反应。PFM有潜力作为免疫佐剂用于化疗患者，而不影响治疗。要点：•干酪乳杆菌CRL431发酵的牛奶（PFM）减少了卡培他滨的副作用。•PFM刺激的免疫细胞改善了卡培他滨对4T1细胞的毒性。•PFM在小鼠模型中维持了卡培他滨的抗癌/抗转移作用。图形摘要。
