Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism.

Abstract

Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment.

• Authors: Xiaomu Wu, Fajiu Li, Xiaojiang Wang, Chenghong Li, Qinghua Meng, Chuanhai Wang, Jie Huang, Shi Chen, Ziyang Zhu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 495 Issue 1 Pg. 267-272 (01 01 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29107691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Antineoplastic Agents
• Diarylquinolines
• bedaquiline
• Adenosine Triphosphate

Topics

• A549 Cells
• Adenosine Triphosphate (metabolism)
• Animals
• Anti-Bacterial Agents (administration & dosage)
• Antineoplastic Agents (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Diarylquinolines (administration & dosage)
• Dose-Response Relationship, Drug
• Energy Metabolism (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, SCID
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Treatment Outcome