4-O-Methylascochlorin Synergistically Enhances 5-Fluorouracil-Induced Apoptosis by Inhibiting the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer Cells

4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus , shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investi...

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Published in:International journal of molecular sciences 2024-06, Vol.25 (11), p.5746
Main Authors: Jo, Min-Young, Jeong, Yun-Jeong, Song, Kwon-Ho, Choi, Yung Hyun, Kwon, Taeg Kyu, Chang, Young-Chae
Format: Article
Language:English
Subjects:
Antibiotics
Apoptosis
Apoptosis - drug effects
beta Catenin - genetics
beta Catenin - metabolism
Cancer
Cancer cells
Cancer therapies
Cell death
Cell Line, Tumor
Cell Proliferation - drug effects
Chemotherapy
Colorectal cancer
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Cytotoxicity
Drug resistance
Drug Resistance, Neoplasm - drug effects
Drug Synergism
Ethylenediaminetetraacetic acid
Fluorouracil
Fluorouracil - pharmacology
Humans
Medical prognosis
Morphology
Oncology, Experimental
Phenols
Phosphorylation
Proteins
RNA
TOR Serine-Threonine Kinases - metabolism
Toxicity
Wnt Signaling Pathway - drug effects
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Summary:4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus , shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25115746