Combinatorial Effects of 5-Fluorouracil and Menadione on Wnt/β-Catenin Pathway in Human Colorectal Cancer Cells.

IF 3.1 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Applied Biochemistry and Biotechnology Pub Date : 2024-10-15 DOI:10.1007/s12010-024-05072-5
Vidya P Warrier, Sankaran Venkatachalam, Ramasamy Sakthivel, M Michael Gromiha, Devarajan Karunagaran
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Abstract

The incidence and mortality rates of colorectal cancer (CRC) are alarmingly high, and the scientific community is consistently engaged in developing newer therapeutic options for cancer cure or prevention. The fluoropyrimidine drug, 5-fluorouracil (5FU), remains the first line of treatment against CRC; nevertheless, relapses frequently occur since the cells gain resistance over time through various mechanisms. Studies have highlighted the significance of combinatorial treatment of a Wnt signaling inhibitor and 5FU as a better treatment strategy to overcome 5FU resistance. Small molecules that specifically target and disrupt β-catenin-TCF interaction, a crucial step of the Wnt signaling, are promising in CRC treatment. In this study, we investigated the synergistic cytotoxic activity of menadione with 5FU as the former has previously been shown to downregulate Wnt signaling in CRC cells. Docking and experimental results suggest that the drug combination interfered with key protein-protein interactions in the β-catenin-TCF complex, exerted synergistic anti-cancerous effects in CRC cells, and downregulated the expression of Wnt signaling proteins. Taken together, our data suggest that the simultaneous binding of 5FU and menadione to β-catenin can block Wnt signaling by disrupting β-catenin-TCF interaction and inhibit the proliferation of CRC cells.

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5-Fluorouracil 和 Menadione 对人类结直肠癌细胞中 Wnt/β-Catenin 通路的联合影响
结直肠癌(CRC)的发病率和死亡率之高令人震惊,科学界一直致力于开发新的癌症治疗或预防方案。氟嘧啶类药物 5-氟尿嘧啶(5FU)仍然是治疗 CRC 的一线药物;然而,由于细胞会随着时间的推移通过各种机制产生抗药性,因此经常会出现复发。研究强调,Wnt 信号抑制剂和 5FU 的联合治疗是克服 5FU 耐药性的更好治疗策略。特异性靶向和破坏β-catenin-TCF相互作用(Wnt信号转导的关键步骤)的小分子有望用于CRC的治疗。在本研究中,我们研究了甲萘醌与 5FU 的协同细胞毒性活性,因为前者曾被证明能下调 CRC 细胞的 Wnt 信号转导。对接和实验结果表明,该药物组合干扰了β-catenin-TCF复合物中的关键蛋白-蛋白相互作用,在CRC细胞中发挥了协同抗癌作用,并下调了Wnt信号蛋白的表达。综上所述,我们的数据表明,5FU和甲萘醌同时与β-catenin结合,可通过破坏β-catenin-TCF的相互作用阻断Wnt信号传导,抑制CRC细胞的增殖。
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来源期刊
Applied Biochemistry and Biotechnology
Applied Biochemistry and Biotechnology 工程技术-生化与分子生物学
CiteScore
5.70
自引率
6.70%
发文量
460
审稿时长
5.3 months
期刊介绍: This journal is devoted to publishing the highest quality innovative papers in the fields of biochemistry and biotechnology. The typical focus of the journal is to report applications of novel scientific and technological breakthroughs, as well as technological subjects that are still in the proof-of-concept stage. Applied Biochemistry and Biotechnology provides a forum for case studies and practical concepts of biotechnology, utilization, including controls, statistical data analysis, problem descriptions unique to a particular application, and bioprocess economic analyses. The journal publishes reviews deemed of interest to readers, as well as book reviews, meeting and symposia notices, and news items relating to biotechnology in both the industrial and academic communities. In addition, Applied Biochemistry and Biotechnology often publishes lists of patents and publications of special interest to readers.
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