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.
Highlights
Retinoblastoma is the most common childhood primary intraocular cancer, which occurs in 1/15, 000 live births worldwide[1]
To determine whether the inhibitory effects of tigecycline on retinoblastoma cell and human retinal microvascular endothelial cell (HREC) is mediated by a similar mechanism, we investigated the mitochondrial translation via examining protein and mRNA levels of cytochrome c oxidase-1, 2 and 4 (Cox-1, Cox-2 and Cox-4, respectively)
To investigate whether the data obtained from in vitro cell culture system are reproducible in in vivo, we investigated the effects of tigecycline on retinoblastoma growth and retinoblastoma angiogenesis in xenograft mouse model
Summary
Retinoblastoma is the most common childhood primary intraocular cancer, which occurs in 1/15, 000 live births worldwide[1]. Retinoblastoma is a heterogeneous disease with aberrant activation of oncogenes and suppression of the tumour suppressor genes, such as retinoblastoma 14. The ideal therapeutic strategies for retinoblastoma are to target both tumor cells and angiogenesis. Substantial evidence on pre-clinical models demonstrate that tigecycline is a novel type of anti-cancer drug. Tigecycline effectively kills leukaemias, renal and liver cancer cells, and significantly augments chemotherapy agents in vitro and in vivo[11,12,13]. The mechanisms of tigecycline in cancer cells include inhibition of mitochondrial translation and Wnt/β-catenin, and autophagy activation[11,14,15]. Retinoblastoma growth, survival and angiogenesis via inhibiting mitochondrial translation, and inducing mitochondrial dysfunctions and oxidative damage
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