白细胞介素(IL)-6的过量产生是结直肠癌(CRC)中恶性肿瘤和耐药性的驱动因素。我们的研究调查了抗炎药治疗后7周,Diacein(Diac),单独或与5-氟尿嘧啶(5-FU)联合使用,使用1,2-二甲基肼(DMH)大鼠CRC模型。单独使用Diac和5-FUDiac可降低癌胚抗原(CEA)的血清水平,虽然所有方案都降低了结肠癌特异性抗原(CCSA)的血清水平,更具体的CRC生物标志物。此外,Diac,5-FU及其组合抑制IL-6的结肠含量/基因表达,其下游癌基因,Kirsten大鼠肉瘤病毒癌基因同源物(K-Ras),因此,Notch细胞内结构域和核因子-κB(NF-κB)p65。反过来,NF-κB下游因子,viz.,基质金属蛋白酶-9(MMP-9),血管内皮生长因子(VEGF),c-Myc,B细胞淋巴瘤-2(Bcl-2)也下调,而E-cadherin升高。此外,这些药物降低了CD31的免疫反应性,以证明它们的抗血管生成作用,而TUNEL测定证实了凋亡效应。通过转移酶dUTP缺口末端标记测定证实了凋亡作用。此外,这些药物抑制p-Akt的结肠含量,β-连环蛋白,和细胞周期蛋白D1免疫反应性。这些药物还激活了肿瘤抑制糖原合成酶激酶3-β(GSK3-β)并上调了Nur77基因的表达,其代表IL-6信号传导的第二臂。然而,只有5-FU上调miR-200a,另一个K-Ras下游因子。体外细胞毒性和迁移/侵袭测定验证了分子轨迹。因此,我们评估了Diac单独的抗肿瘤作用及其加入5-FU后可能的化学增敏作用.这种组合可能针对关键的致癌途径,包括IL-6/K-Ras/Notch/NF-κBp65轴,p-Akt/GSK3-β/β-连环蛋白/细胞周期蛋白D-1中心,Nur77
Excessive interleukin (IL)-6 production is a driver for malignancy and drug resistance in colorectal cancer (CRC). Our study investigated a seven-week post-treatment with the anti-inflammatory drug, Diacerein (Diac), alone or in combination with 5-fluorouracil (5-FU), using a 1,2-dimethylhydrazine (DMH) rat model of CRC. Diac alone and 5-FU+Diac reduced serum levels of carcino-embryonic antigen (CEA), while all regimens decreased serum levels of colon cancer-specific antigen (CCSA), a more specific CRC biomarker. Additionally, Diac, 5-FU and their combination suppressed colonic content/gene expression of IL-6, its downstream oncogene, Kirsten rat sarcoma viral oncogene homolog (K-Ras), and consequently Notch intracellular domain and nuclear factor-kappa B (NF-κB) p65. In turn, NF-κB downstream factors, viz., matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), c-Myc, and B-cell lymphoma-2 (Bcl-2) were also downregulated, while E-cadherin was elevated. Additionally, the drugs reduced the immunoreactivity of CD31 to prove their anti-angiogenic effect, while the TUNEL assay confirmed the apoptotic effect. The apoptotic effect was confirmed by transferase dUTP nick-end labeling assay. Moreover, these drugs inhibited colon content of p-Akt, β-catenin, and cyclin D1 immunoreactivity. The drugs also activated the tumor suppressor glycogen synthase kinase 3- β (GSK3-β) and upregulated the expression of the Nur77 gene, which represents the second arm of IL-6 signaling. However, only 5-FU upregulated miR-200a, another K-Ras downstream factor. The in-vitro cytotoxic and migration/invasion assays verified the molecular trajectories. Accordingly, we evaluated the antineoplastic effect of Diac alone and its possible chemosensitization effect when added to 5-FU. This combination may target critical oncogenic pathways, including the IL-6/K-Ras/Notch/NF-κB p65 axis, p-Akt/GSK3-β/β-catenin/cyclin D-1 hub, and Nur77.