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DGG-300273, a novel WNT/β-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.
- Source :
- Investigational New Drugs; Feb2023, Vol. 41 Issue 1, p105-114, 10p
- Publication Year :
- 2023
-
Abstract
- Summary: Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/β-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/β-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/β-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study. [ABSTRACT FROM AUTHOR]
- Subjects :
- COLON tumors
ACETYLCYSTEINE
CELL culture
STAINS & staining (Microscopy)
COLONY-forming units assay
WESTERN immunoblotting
WNT proteins
APOPTOSIS
INVESTIGATIONAL drugs
CELLULAR signal transduction
CELL survival
T-test (Statistics)
DESCRIPTIVE statistics
RESEARCH funding
CELL lines
DRUG development
REACTIVE oxygen species
TUMOR markers
MOLECULAR structure
CASPASES
CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 41
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Investigational New Drugs
- Publication Type :
- Academic Journal
- Accession number :
- 162584892
- Full Text :
- https://doi.org/10.1007/s10637-022-01295-7