Kwiatkowska Iwona, Hermanowicz Justyna Magdalena, Czarnomysy Robert, Surażyński Arkadiusz, Kowalczuk Krystyna, Kałafut Joanna, Przybyszewska-Podstawka Alicja, Bielawski Krzysztof, Rivero-Müller Adolfo, Mojzych Mariusz, Pawlak Dariusz
Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.
Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.
Cancers (Basel). 2023 Dec 26;16(1):122. doi: 10.3390/cancers16010122.
(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：本研究的目的是检测1,2,4-三嗪衍生物MM-129与犬尿氨酸途径抑制剂吲哚莫德（IND）联合给药对结肠癌的抗肿瘤活性。(2) 方法：在异种移植的斑马鱼胚胎中评估所研究化合物联合给药的效果。然后，评估化合物联合给药对细胞活力、凋亡和细胞内信号通路等细胞过程的影响。使用两种结肠癌细胞系，即DLD-1和HT-29进行体外研究。(3) 结果：结果表明，MM-129和吲哚莫德同时应用可在斑马鱼异种移植中更强烈地抑制肿瘤生长。这些化合物的组合通过降低线粒体电位、增强磷脂酰丝氨酸（PS）外化和激活半胱天冬酶来强化凋亡过程。此外，在应用的化合物组合作用下，蛋白激酶B（AKT）和吲哚胺2,3-双加氧酶-1（IDO1）的表达受到干扰。(4) 结论：同时靶向促进肿瘤进展的持续细胞信号传导以及抑制犬尿氨酸途径酶IDO1，可增强受试化合物对结肠癌细胞的抗肿瘤作用。
