Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells

Yadunandam,Anandam  Kasin; Yoon,Jin-Soo; Jeong,Yeon  Tae; Kim,Woe-Yeon; Lee,Sang-Yeol; Kim,Gun-Do

doi:10.3892/ijmm.2015.2240

Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells

Authors:
- Anandam Kasin Yadunandam
- Jin-Soo Yoon
- Yeon Tae Jeong
- Woe-Yeon Kim
- Sang-Yeol Lee
- Gun-Do Kim
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Affiliations: Department of Microbiology, College of Natural Sciences, Pukyong National University, Busan 608-737, Republic of Korea, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia, Department of Image Science and Engineering, College of Engineering, Pukyong National University, Busan 608-737, Republic of Korea, Division of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju 660-701, Republic of Korea
Published online on: June 9, 2015 https://doi.org/10.3892/ijmm.2015.2240
Pages: 577-587

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Abstract

In continuation of previous efforts to investigate the biological potency of tetrahydropyridinol derivatives, the present study synthesized three target compounds: N-(bromoacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetra-hydropyridine (5a), N-(chloroacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5b) and N-(2-bromopropanoyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5c), and examined their anticancer potency. Experiments were performed using the Sk-Hep1 and Hep3B human hepatocellular carcinoma cell lines and MDA-MB-231 breast adenocarcinoma cell line. Among the three compounds, 5a and 5b were comparably and significantly cytotoxic to the Sk-Hep1, Hep3B and MDA-MB-231 cells. The highest level of cytotoxicity was detected in theSk-Hep1 cells with half maximal inhibitory concentrations for compounds 5a and 5b at 12 and 6 µM, respectively. These two compounds induced cell cycle arrest in the Sk-Hep1 and MDA-MB-231 cells through the downregulation of β-catenin and upregulation of glycogen synthase kinase-3β and E-cadherin. By contrast, 5a and 5b induced G1 arrest in the Hep3B cells by modulating the p21 and p27 cell cycle regulatory molecules and cyclin-dependent kinase 2. In addition, 5a and 5b significantly inhibited the invasion of Sk-Hep1 and MDA-MB-231 cells. These results suggested that the 5a and 5b compounds induce cell cycle arrest by suppressing Wnt/β-catenin signaling in highly invasive Sk-Hep1 and MDA-MB-231 cells, and by inducing p53 independent cell cycle arrest in Hep3B cells.

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