Sitagliptin synergizes 5-fluorouracil efficacy in colon cancer cells through MDR1-mediated flux impairment and down regulation of NFκB2 and p-AKT survival proteins

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2024-08-01 DOI:10.1002/jbt.23796

Asmaa Eisa, Shaden M. Hanafy, Hany Khalil, Mohamed F. Elshal

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引用次数: 0

Abstract

5-fluorouracil (5-FU) is an inexpensive treatment for colon cancer; however, its efficacy is limited by chemoresistance. This study investigates the combination therapy approach of 5-FU with Sitagliptin (Sita), a diabetic drug with potential cancer-modulating effects. The combination was evaluated in vitro and in silico, focusing on the effects of Sita and 5-FU on colon cancer cells. The results showed that the addition of Sita significantly decreased the IC50 of 5-FU compared to 5-Fu monotherapy. The study also found that Sita and 5-FU interact synergistically, with a combination index below 1. Sita successfully lowered the 5-FU dosage reduction index, decreasing the expression of MDR1 mRNA and p-AKT and NFκB2 subunits p100/p52 protein. Molecular docking analyses confirmed Sita's antagonistic action on MDR1 and thymidylate synthase proteins. The study concludes that sitagliptin can target MDR1, increase apoptosis, and significantly reduce the expression of p-AKT and NFκB2 cell-survival proteins. These effects sensitize colon cancer cells to 5-FU. Repurposing sitagliptin may enhance the anticancer effects of 5-FU at lower dosages.

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西他列汀通过MDR1介导的通量损伤以及NFκB2和p-AKT存活蛋白的下调协同5-氟尿嘧啶对结肠癌细胞的疗效。

5-氟尿嘧啶（5-FU）是治疗结肠癌的一种廉价疗法，但其疗效受到化疗耐药性的限制。本研究探讨了 5-FU 与西他列汀（Sita）的联合治疗方法，西他列汀是一种具有潜在癌症调节作用的糖尿病药物。研究人员对这种联合疗法进行了体外和硅学评估，重点研究了西他和 5-FU 对结肠癌细胞的影响。结果显示，与 5-Fu 单药治疗相比，添加 Sita 能显著降低 5-FU 的 IC50。研究还发现，Sita 和 5-FU 具有协同作用，联合指数低于 1。Sita 成功降低了 5-FU 的剂量减少指数，减少了 MDR1 mRNA 以及 p-AKT 和 NFκB2 亚基 p100/p52 蛋白的表达。分子对接分析证实了西他对 MDR1 和胸腺嘧啶合成酶蛋白的拮抗作用。研究得出结论，西他列汀可以靶向 MDR1，增加细胞凋亡，并显著降低 p-AKT 和 NFκB2 细胞存活蛋白的表达。这些作用使结肠癌细胞对 5-FU 敏感。对西他列汀进行再利用可能会以较低的剂量增强5-FU的抗癌效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.