bufotalin and Lung-Neoplasms

Ferroptosis is a new form of regulated cell death that is dependent on iron- and lipid reactive oxygen species. Emerging evidence indicate that induction of ferroptosis could inhibit the proliferation of diverse cancer cells, which functions as a potent tumor suppressor in cancer. Here, we firstly reported Bufotalin (BT), a natural small molecule, was a novel glutathione peroxidase 4 (GPX4) inhibitor, which could trigger the ferroptosis in non-small cell lung cancer cells. In vitro, BT significantly inhibited the proliferation of A549 cells and induced the ferroptosis, whereas ferroptosis inhibitor or iron chelator significantly reversed the cytotoxicity of BT on A549 cells. Moreover, BT also increased the intracellular Fe

Topics: Bufanolides; Carcinoma, Non-Small-Cell Lung; Ferroptosis; Humans; Lipid Peroxidation; Lung Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Ubiquitination

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.. 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.. 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.. Our study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.

Topics: Amphibian Venoms; Animals; Bufanolides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclooxygenase 2; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Phosphorylation; Promoter Regions, Genetic; Protein Conformation; Xenograft Model Antitumor Assays