Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/β-Catenin in Colon Cancer Cells
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Published on: October 27, 2014
Yu Zou1, Yuying He1, Lijuan Tan1
1Institute of Pharmaceutical Process, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei Province, China.
Abstract:
Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.
Insights
New piperlongumine derivatives release nitric oxide (NO), enhancing cancer cell death. Compound 5 showed potent antiproliferative effects against colon cancer by targeting the Wnt/β-catenin pathway.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Piperlongumine induces cancer cell apoptosis by increasing reactive oxygen species (ROS).
- Nitric oxide (NO) donors exhibit anticancer activity, amplified by ROS in the tumor microenvironment.
- Synergistic strategies combining NO release and piperlongumine derivatives are explored for enhanced anticancer effects.
Purpose of the Study:
- To design and synthesize novel NO-releasing piperlongumine derivatives.
- To evaluate the antiproliferative activity and NO-releasing capacity of these derivatives.
- To investigate the mechanism of action, focusing on the Wnt/β-catenin pathway.
Main Methods:
- Synthesis of NO-releasing piperlongumine derivatives (compounds 2-5) and a non-NO-releasing control (compound 6).
- Assessment of antiproliferative activity against HCT-116 colon cancer cells.
- Measurement of NO release in cancer cells.
- Analysis of β-catenin expression and Wnt/β-catenin pathway modulation.
Main Results:
- Compound 5 demonstrated the most potent antiproliferative activity against HCT-116 cells.
- Compound 5 efficiently released NO in the tested colon cancer cell line.
- Compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression.
Conclusions:
- NO-releasing piperlongumine derivatives show promise as anticancer agents.
- Compound 5 is a potential therapeutic candidate for colon cancer targeting the Wnt/β-catenin pathway.
- The combination of NO release and piperlongumine derivatives enhances anticancer efficacy.
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