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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Demethylzeylasteral Exerts Antitumor Effects via Disruptive Autophagic Flux and Apoptotic Cell Death in Human Colorectal Cancer Cells and Increases Cell Chemosensitivity to 5-Fluorouracil

Author(s): Guiyuan Liu, Dengxiang Lai, Yi Jiang, Hongjing Yang, Hui Zhao, Yonghui Zhang, Dan Liu and Yi Pang*

Volume 22, Issue 5, 2022

Published on: 08 June, 2021

Page: [851 - 863] Pages: 13

DOI: 10.2174/1871520621666210608104021

Price: $65

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Abstract

Background: Demethylzeylasteral (ZST93), a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF), has been reported to exert antineoplastic effects in several cancer cell types. However, the anti-tumour effects of ZST93 in human colorectal cancer (CRC) cells are unknown.

Objective: The aim of the present study was to evaluate the antitumor effects of ZST93 on cell cycle arrest, disruptive autophagic flux, apoptotic cell death and enhanced chemosensitivity to 5-FU in human CRC cells.

Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, colony formation assay, flow cytometry, immunoblotting, immunofluorescence, 5-ethynyl-20-deoxyuridine (EdU) incorporation assay and autophagy analysis were used to evaluate the effects of ZST93 on cell viability, cell cycle progression, apoptosis and autophagy in two human CRC cell lines. Moreover, ZST93’s combined anti-tumour effects with 5-fluorouracil (5-FU) were evaluated.

Results: ZST93 inhibited CRC cell proliferation and growth. It was responsible for blocked cell cycle transition by arresting CRC cells in the G0/G1 phase via down-regulation of CDK4, CDK6, Cyclin D1 and c-MYC. Moreover, ZST93 induced suppressive autophagic flux and caspase-3-dependent cell death, which was further strengthened by the blocking of the autophagy process using chloroquine (CQ). Moreover, ZST93 enhanced CRC cells’ chemosensitivity to 5-FU via modulation of autophagy and apoptosis.

Conclusion: ZST93 exerts anti-tumor effects via disruptive autophagic flux and apoptotic cell death in human CRC cells and increases cell chemosensitivity to 5-FU. These results provide insights into the utilisation of ZST93 as an adjuvant or direct autophagy inhibitor and suggest ZST93 as a novel therapeutic strategy for treating CRC.

Keywords: Demethylzeylasteral (ZST93), colorectal cancer, apoptosis, autophagic flux, 5-fluorouracil (5-FU), chemosensitivity.

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