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

Abstract

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.

• Authors: Sheng Kai, Jia-Huan Lu, Ping-Ping Hui, Hui Zhao
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 452 Issue 3 Pg. 768-74 (Sep 26 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25201730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Bufanolides
• Cyclophilin D
• Lactones
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• PPIF protein, mouse
• RNA, Small Interfering
• Spiro Compounds
• sanglifehrin A
• Cyclosporine
• Cyclophilins
• cinobufotalin

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Bufanolides (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclophilin D
• Cyclophilins (antagonists & inhibitors, genetics, metabolism)
• Cyclosporine (pharmacology)
• Drug Evaluation, Preclinical
• Gene Expression Regulation, Neoplastic
• Humans
• Lactones (pharmacology)
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, genetics, metabolism)
• Mitochondrial Permeability Transition Pore
• RNA, Small Interfering (genetics, metabolism)
• Spiro Compounds (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays