The anti-malarial atovaquone selectively increases chemosensitivity in retinoblastoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition

Journal Article · Mon Oct 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.06.049· OSTI ID:23103526

Ke, Feng; Yu, Jinqiang ^[1]; Chen, Wei ^[2]; Si, Xiaomin ^[3]; Li, Xinhui ^[4]; Yang, Fang ^[1]; Liao, Yingying ^[5]; Zuo, Zhigang ^[6]

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1. Department of Ophthalmology, Renmin Hospital, Hubei University of Medicine, Shiyan (China)
2. Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Hubei (China)
3. Department of Cardiopulmonary Rehabilitation, Renmin Hospital, Hubei University of Medicine, Shiyan (China)
4. Department of Oncology, Shiyan Taihe Hospital, Shiyan (China)
5. Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan (China)
6. Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan (China)

Highlights: • Anti-malarial atovaquone exhibits preferential toxicity to retinoblastoma cells. • Atovaquone increases chemosensitivity in retinoblastoma. • Retinoblastoma cells have higher mitochondrial biogenesis than normal retinal cells. • Atovaquone targets Akt/AMPK/mTOR signaling via inducing mitochondrial dysfunction. • Mitochondrial respiration inhibition is required for atovaquone's action. Mitochondria has been identified as a promising target in several cancers. However, little is known on the effects of targeting mitochondria in retinoblastoma. In this work, we show that anti-malarial atovaquone, at clinically achievable concentration, demonstrates inhibitory effects to retinoblastoma cells, to a more extent than in normal retinal cells. Atovaquone also significantly increases chemosensitivity in retinoblastoma. Importantly, we show that retinoblastoma cells have higher level of mitochondrial respiration, membrane potential, mass and ATP compared to normal retinal cells. Although atovaquone significantly inhibits mitochondrial respiration and decrease ATP level in both malignant and normal retinal cells in a similar manner, atovaquone induces much more oxidative stress and damage in retinoblastoma than normal retinal cells. These suggest that normal retinal cells are more tolerable to mitochondrial dysfunctions than retinoblastoma cells. We further demonstrate that atovaquone targets Akt/AMPK/mTOR signaling via inducing mitochondrial dysfunction. Our pre-clinical work demonstrates the translational potential of atovaquone as an addition to the treatment armamentarium for retinoblastoma. Our work also demonstrates the differences of mitochondrial biogenesis and function in malignant versus normal retinal cells which are important for the targeted therapy in retinoblastoma.

• OSTI ID: 23103526
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 504; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
MITOCHONDRIA
NEOPLASMS
RESPIRATION
RETINA
TOXICITY