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Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB
Zhenlong Yu, Wei Guo, Xiaochi Ma1
1Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian 116044, China. maxc1978@163.com.
Background:
Gamabufotalin (CS-6), a major bufadienolide of Chansu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, the underlying mechanism of CS-6 involved in anti-tumor activity remains poorly understood.
Methods:
The biological functions of gamabufotalin (CS-6) were investigated by migration, colony formation and apoptosis assays in NSCLC cells. The nuclear localization and interaction between transcriptional co-activator p300 and NF-κB p50/p65 and their binding to COX-2 promoter were analyzed after treatment with CS-6. Molecular docking study was used to simulate the interaction of CS-6 with IKKβ. The in vivo anti-tumor efficacy of CS-6 was also analyzed in xenografts nude mice. Western blot was used to detect the protein expression level.
Results:
Gamabufotalin (CS-6) strongly suppressed COX-2 expression by inhibiting the phosphorylation of IKKβ via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. In addition, CS-6 induced apoptosis by activating the cytochrome c and caspase-dependent apoptotic pathway. Moreover, CS-6 markedly down-regulated the protein levels of COX-2 and phosphorylated p65 NF-κB in tumor tissues of the xenograft mice, and inhibited tumor weight and size.
Conclusions:
Our study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.
Insights
Gamabufotalin (CS-6) suppresses lung cancer growth by inhibiting COX-2 expression and activating apoptosis. This natural compound shows promise for treating COX-2-mediated diseases like lung cancer.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Gamabufotalin (CS-6), a bufadienolide from Chansu, is recognized for cancer therapy due to its stability and safety.
- The precise anti-tumor mechanisms of CS-6 are not fully elucidated.
Purpose of the Study:
- To investigate the anti-tumor mechanisms of gamabufotalin (CS-6) in non-small cell lung cancer (NSCLC).
- To evaluate the efficacy of CS-6 in preclinical models of lung cancer.
Main Methods:
- In vitro assays (migration, colony formation, apoptosis) and in vivo xenograft models were employed.
- Analysis included protein expression (Western blot), nuclear localization, protein interactions, and molecular docking.
- Specific targets investigated were COX-2, IKKβ, p300, and NF-κB signaling pathway.
Main Results:
- CS-6 inhibited COX-2 expression by blocking IKKβ phosphorylation, preventing NF-κB and p300 binding to the COX-2 promoter.
- CS-6 induced apoptosis via the cytochrome c and caspase-dependent pathways.
- In vivo, CS-6 reduced tumor growth, size, and weight, with decreased COX-2 and phosphorylated p65 NF-κB levels.
Conclusions:
- CS-6 demonstrates significant anti-tumor activity against lung cancer.
- The findings support CS-6 as a potential therapeutic agent for COX-2-related cancers, including lung cancer.
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