Journal
MOLECULAR CANCER
Volume 13, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1476-4598-13-203
Keywords
Gamabufotalin; NSCLC; COX-2; NF-kappa B; p300; IKK beta
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Funding
- National Natural Science Foundation of China [81274047, 81473334, 81301721, 81272195, 81071687]
- State 973 Program of China [2014CB542005]
- Education Department of Liaoning Province, China [LR2014025]
- Dalian Outstanding Youth Science and Technology Talent
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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-kappa B 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 IKK beta. 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 IKK beta via targeting the ATP-binding site, thereby abrogating NF-kappa B 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-kappa B 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.
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