A novel drug prejudice scaffold-imidazopyridine-conjugate can promote cell death in a colorectal cancer model by binding to β-catenin and suppressing the Wnt signaling pathway,Journal of Advanced Research

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A novel drug prejudice scaffold-imidazopyridine-conjugate can promote cell death in a colorectal cancer model by binding to β-catenin and suppressing the Wnt signaling pathway
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-07-25 , DOI: 10.1016/j.jare.2024.07.022
Min Hee Yang ₁ , Basappa Basappa ₂ , Suresha N Deveshegowda ₂ , Akshay Ravish ₂ , Arunkumar Mohan ₂ , Omantheswara Nagaraja ₃ , Mahendra Madegowda ₃ , Kanchugarakoppal S Rangappa ₂ , Amudha Deivasigamani ₄ , Vijay Pandey ₅ , Peter E Lobie ₅ , Kam Man Hui ₄ , Gautam Sethi ₆ , Kwang Seok Ahn ₁

Affiliation

Introduction

Globally, colorectal cancer (CRC) is the third most common type of cancer, and its treatment frequently includes the utilization of drugs based on antibodies and small molecules. The development of CRC has been linked to various signaling pathways, with the Wnt/β-catenin pathway identified as a key target for intervention.

Objectives

We have explored the impact of imidazopyridine-tethered chalcone-C (CHL-C) in CRC models.

Methods

To determine the influence of CHL-C on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the Wnt/β-catenin signaling pathway and the anti-cancer effects of CHL-C in vivo were examined in an orthotopic HCT-116 mouse model.

Results

We describe the synthesis and biological assessment of the CHL series as inhibitors of the viability of HCT-116, SW480, HT-29, HCT-15, and SNU-C2A CRC cell lines. Further biological evaluations showed that CHL-C induced apoptosis and autophagy in down-regulated β-catenin, Wnt3a, FZD-1, Axin-1, and p-GSK-3β (Ser9), and up-regulated p-GSK3β (Tyr216) and β-TrCP. In-depth analysis using structure-based bioinformatics showed that CHL-C strongly binds to β-catenin, with a binding affinity comparable to that of ICG-001, a well-known β-catenin inhibitor. Additionally, our in vivo research showed that CHL-C markedly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues.

Conclusion

CHL-C is capable of inducing apoptosis and autophagy by influencing the Wnt/β-catenin signaling pathway.

中文翻译：

一种新的药物偏见支架-咪唑吡啶偶联物可以通过与 β-catenin 结合并抑制 Wnt 信号通路来促进结直肠癌模型中的细胞死亡

介绍

在全球范围内，结直肠癌（CRC）是第三大最常见的癌症类型，其治疗通常包括使用基于抗体和小分子的药物。CRC 的发展与各种信号通路有关，其中 Wnt/β-catenin 通路被确定为干预的关键靶点。

目标

我们探讨了咪唑吡啶栓系查尔酮-C （CHL-C）在 CRC 模型中的影响。

方法

为确定 CHL-C 对细胞凋亡和自噬的影响，进行 Western blot 分析、膜联蛋白 V 测定、细胞周期分析、吖啶橙染色和免疫细胞化学。接下来，在原位 HCT-116 小鼠模型中检查 Wnt/β-catenin 信号通路的激活和 CHL-C 在体内的抗癌作用。

结果

我们将 CHL 系列的合成和生物学评估描述为 HCT-116、SW480、HT-29、HCT-15 和 SNU-C2A CRC 细胞系活力的抑制剂。进一步的生物学评估表明，CHL-C 诱导下调的 β-catenin、Wnt3a、FZD-1、Axin-1 和 p-GSK-3β （Ser9）的细胞凋亡和自噬，以及上调的 p-GSK3β （Tyr216）和 β-TrCP。使用基于结构的生物信息学的深入分析表明，CHL-C 与 β-catenin 强烈结合，其结合亲和力与众所周知的 β-catenin 抑制剂 ICG-001 的结合亲和力相当。此外，我们的体内研究表明，CHL-C 显着抑制肿瘤生长并触发肿瘤组织中细胞凋亡和自噬的激活。