양민희 (경희대학교, 한의과대학)

한빛사논문

조회300

경희대학교, 한의과대학

CV File 196 kb

J. Adv. Res., Available online 25 July 2024 | https://doi.org/10.1016/j.jare.2024.07.022 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

Min Hee Yang ^a,1, Basappa Basappa ^b,1, Suresha N. Deveshegowda ^b, Akshay Ravish ^b, Arunkumar Mohan ^b, Omantheswara Nagaraja ^c, Mahendra Madegowda ^c, Kanchugarakoppal S. Rangappa ^b, Amudha Deivasigamani ^d, Vijay Pandey ^e,f,g, Peter E. Lobie ^e,f,g, Kam Man Hui ^d, Gautam Sethi ^h, Kwang Seok Ahn^a

^aDepartment of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea

^bLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India

^cDepartment of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India

^dDivision of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610, Singapore

^eShenzhen Bay Laboratory, Shenzhen 518055, China

^fTsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China

^gInstitute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China

^hDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore

¹These authors contributed equally to this study.

Corresponding authors: Kam Man Hui, Gautam Sethi, Kwang Seok Ahn

Abstract

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.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-26)
연구진국내 연구진
분야 의약학 > 약학

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