(1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells.
（1）背景：本研究旨在探讨1,2,4-三嗪衍生物MM-129与犬尿氨酸通路抑制剂吲哚莫德（IND）联合给药对结肠癌的抗肿瘤活性。（2）方法：通过斑马鱼异种移植胚胎模型评估两种化合物联合给药的疗效，进而分析联合用药对细胞活力、凋亡及细胞内信号通路等细胞过程的影响。体外研究采用DLD-1和HT-29两种结直肠癌细胞系进行。（3）结果：联合应用MM-129与吲哚莫德可显著增强对斑马鱼移植瘤生长的抑制作用。该组合通过降低线粒体膜电位、增强磷脂酰丝氨酸（PS）外翻及激活半胱天冬酶，进而强化细胞凋亡过程。此外，联合用药可干扰蛋白激酶B（AKT）与吲哚胺2,3-双加氧酶1（IDO1）的表达。（4）结论：同步靶向促进肿瘤进展的细胞信号通路与抑制犬尿氨酸通路关键酶IDO1，能显著增强测试化合物对结肠癌细胞的抗肿瘤效应。
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