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Pre-clinical evidence that salinomycin is active against retinoblastoma via inducing mitochondrial dysfunction, oxidative damage and AMPK activation

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Abstract

The poor outcomes in retinoblastoma necessitate new treatments. Salinomycin is an attractive candidate, and has demonstrated selective anti-cancer properties in different cancer types. This work addressed the efficacy of salinomycin in retinoblastoma models and probe the associated mechanisms. Cellular functional assays were conducted to determine the effects salinomycin in vitro. Xenograft retinoblastoma mouse model was established to investigate the efficacy of salinomycin in vivo. Biochemical assays were conducted to analyze the mechanism of salinomycin’s action focusing on mitochondrial functions, energy reduction-related signaling pathways. Salinomycin has positive effects towards retinoblastoma cells regardless of heterogeneity through suppressing growth and inducing apoptosis. Salinomycin also specifically inhibits cells displaying stemness and highly invasive phenotypes. Using retinoblastoma xenograft mouse model, we show that salinomycin at non-toxic dose effectively inhibits growth and induces apoptosis. Mechanistic studies show that salinomycin inhibits mitochondrial respiration via specifically suppressing complex I and II activities, reduces mitochondrial membrane potential and decreases energy reduction, followed by induction of oxidative stress and damage, AMPK activation and mTOR inhibition. Our study highlights that adding salinomycin to the existing treatment armamentarium for retinoblastoma is beneficial.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by Nature Science Foundation of Hubei Province (2016-A06).

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Authors and Affiliations

  1. Department of Ophthalmology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli Street, Wuhan, 430014, Hubei, China

    Jing Li & Yao Min

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  1. Jing Li
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  2. Yao Min
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Contributions

JL and YM designed the experiments; JL performed the experiments and wrote the manuscript; All authors interpreted the data, supervised the project and revised the manuscript.

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Correspondence to Yao Min.

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Research involving human participants and/or animals

This work was approved by the institutional review board of Tongji Medical College, Huazhong University of Science and Technology on 26 August 2018 (Approval No. 2018-C05). This study was conducted in accordance with the Declaration of Helsinki.

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All authors declare no conflict of interest.

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Li, J., Min, Y. Pre-clinical evidence that salinomycin is active against retinoblastoma via inducing mitochondrial dysfunction, oxidative damage and AMPK activation. J Bioenerg Biomembr 53, 513–523 (2021). https://doi.org/10.1007/s10863-021-09915-2

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