Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent

Lung Cancer is a major cause of cancer-related mortality in the United States and around the world. Due to the pre-existing or acquired chemo-resistance, the current standard chemotherapy regimens only show moderate activity against lung Cancer. In the current study, we explored the potential anti-lung Cancer activity of cinobufotalin in vivo and in vitro, and studied the underlying mechanisms. We demonstrated that cinobufotalin displayed considerable cytotoxicity against lung Cancer cells (A549, H460 and HTB-58 lines) without inducing significant cell Apoptosis. Our data suggest that mitochondrial protein Cyclophilin D (Cyp-D)-dependent mitochondrial permeability transition pore (mPTP) opening mediates cinobufotalin-induced non-apoptotic death of lung Cancer cells. The Cyp-D inhibitor cyclosporine A (CsA), the mPTP blocker sanglifehrin A (SfA), and Cyp-D shRNA-silencing significantly inhibited cinobufotalin-induced mitochondrial membrane potential (MMP) reduction and A549 cell death (but not Apoptosis). Using a mice xenograft model, we found that cinobufotalin inhibited A549 lung Cancer cell growth in vivo. Thus, cinobufotalin mainly induces Cyp-D-dependent non-apoptotic death in cultured lung Cancer cells. The results of this study suggest that cinobufotalin might be further investigated as a novel anti-lung Cancer agent.