Tigecycline as a dual inhibitor of retinoblastoma and angiogenesis via inducing mitochondrial dysfunctions and oxidative damage.

Abstract

Retinoblastoma is the most common intraocular malignancy in children with poor prognosis. The progression of retinoblastoma is dependent on a robust angiogenic response. Targeting both retinoblastoma cells and angiogenesis may therefore provide an alternative therapeutic strategy in retinoblastoma. Here, we demonstrated the inhibitory effects of tigecycline, a FDA-approved antibiotic, in retinoblastoma and angiogenesis in vitro and in vivo. We showed that tigecycline significantly inhibited growth and induced caspase-dependent apoptosis of multiple retinoblastoma cell lines. Tigecycline also effectively inhibited angiogenesis through suppressing capillary network formation, migration, proliferation and survival of human retinal microvascular endothelial cell (HREC). Mechanistically, tigecycline acts on both retinoblastoma cells and HREC via inhibiting mitochondrial protein translation, resulting in mitochondrial dysfunction, energy crisis, and oxidative damage. Importantly, we demonstrated the in vivo efficacy of tigecycline in inhibiting retinoblastoma and angiogenesis, and inducing oxidative stress on xenograft mouse model. In addition, ATP levels and growth rates were largely affected in retinoblastoma ρ0 cells that lacked mitochondrial respiration. Our work provides systematic pre-clinical evidence for repurposing tigecycline from its traditional use for retinoblastoma treatment. Our work demonstrates the essential roles of mitochondrial metabolism in both retinoblastoma and its angiogenesis.

• Authors: Ying Xiong, Wei Liu, Qian Huang, Jierong Wang, Yanjun Wang, Huijuan Li, Xuedong Fu
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 11747 (08 06 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30082885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Tigecycline
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Anti-Bacterial Agents (therapeutic use)
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• Flow Cytometry
• Humans
• Immunoblotting
• Mice
• Mice, SCID
• Mitochondria (drug effects, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Oxidative Stress (drug effects)
• Real-Time Polymerase Chain Reaction
• Retinoblastoma (drug therapy, metabolism)
• Tigecycline (therapeutic use)
• Xenograft Model Antitumor Assays