Biophysics Institute, IBILI-Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
Biophysics Institute, IBILI-Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; CIMAGO, FMUC-Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; CNC.IBILI, University of Coimbra, 3000-548 Coimbra, Portugal; Faculty of Sciences and Technology, University of Coimbra, 3030-790 Coimbra, Portugal.
J Nutr Biochem. 2018 Jun;56:183-192. doi: 10.1016/j.jnutbio.2018.02.018. Epub 2018 Mar 3.
A diet rich in fiber is associated with a low risk of developing colorectal cancer. Dietary fiber fermentation by intestinal microflora results in the production of butyrate, which has been reported as a chemopreventive agent and a histone deacetylase inhibitor (HDACi). Irinotecan is used as second-line treatment and induces adverse effects with serious life-threatening toxicities in at least 36% of patients. Our study intends to find a synergy that could improve the efficacy and decrease the toxicity of chemotherapy. Results demonstrate that milimolar concentrations of butyrate has an anti-proliferative effect in all three colon cancer cell lines under study, leading to a decrease on cell viability, expression of P21, P53 and β-catenin, being able to modulate P-glycoprotein activity and to induce apoptosis by modulation of BAX/BCL-2 ratio. Combined therapy has a cytotoxic potential, resulting in a synergistic effect, and allows a reduction in irinotecan concentration needed to reduce IC. This potential was verified in terms of cell viability and death, cell cycle and expression of P21 and P53. Butyrate and irinotecan act synergistically in the three cancer cell lines, despite the different genetic background and location, and inhibited tumor growth in a xenograft model. Butyrate is able to influence the mechanism of LS1034 cell line chemoresistance. Butyrate in combination with chemotherapeutic agents has an important role for the treatment of colorectal cancer. Such understanding can guide decisions about which patients with colorectal cancer may benefit from therapy with butyrate demonstrating the important role of diet in colorectal cancer treatment.
富含纤维的饮食与结直肠癌风险降低有关。膳食纤维被肠道微生物发酵产生丁酸盐，丁酸盐已被报道为一种化学预防剂和组蛋白去乙酰化酶抑制剂（HDACi）。伊立替康被用作二线治疗药物，至少有 36%的患者会产生严重威胁生命的毒性不良反应。我们的研究旨在寻找一种协同作用，以提高化疗的疗效并降低其毒性。结果表明，在所有三种研究的结肠癌细胞系中，丁酸盐的毫摩尔浓度具有抗增殖作用，导致细胞活力下降，P21、P53 和 β-连环蛋白的表达减少，能够调节 P-糖蛋白的活性，并通过调节 BAX/BCL-2 比值诱导细胞凋亡。联合治疗具有细胞毒性潜力，产生协同作用，并允许减少伊立替康浓度以降低 IC。这一潜力在细胞活力和死亡、细胞周期以及 P21 和 P53 的表达方面得到了验证。丁酸盐和伊立替康在三种癌细胞系中协同作用，尽管遗传背景和位置不同，并在异种移植模型中抑制肿瘤生长。丁酸盐能够影响 LS1034 细胞系化疗耐药的机制。丁酸盐联合化疗药物在治疗结直肠癌方面具有重要作用。这种理解可以指导哪些结直肠癌患者可能从丁酸盐治疗中获益的决策，证明了饮食在结直肠癌治疗中的重要作用。
