Sunitinib-induced oxidative imbalance and retinotoxic effects in rats
Álvaro Santana-Garrido1, Claudia Reyes-Goya2, Helder André3
1Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, CL Profesor García González 2, 41012 Sevilla, Spain; Epidemiología Clínica y Riesgo Cardiovascular, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío - Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain.
Aims:
Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals.
Main Methods:
Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR.
Key Findings:
NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase.
Significance:
This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions.
Insights
Sunitinib (Su) treatment increases oxidative stress in the eye by activating NADPH oxidase. This may lead to retinotoxicity and sight-threatening conditions, necessitating careful monitoring during long-term use.
Area of Science:
- Ophthalmology
- Pharmacology
- Molecular Biology
Background:
- Sunitinib (Su) is a tyrosine kinase inhibitor used as an anti-angiogenic drug.
- Systemic Su exposure can cause retinal detachment and photoreceptor damage.
- The role of oxidative stress in Su-induced ocular toxicity requires further investigation.
Purpose of the Study:
- To investigate the involvement of the NADPH oxidase system and oxidative stress in the eyes of rats treated with Sunitinib.
- To determine the impact of Su on key enzymes and signaling pathways related to oxidative stress in ocular tissues.
Main Methods:
- Male Wistar rats received 25 mg/kg/day of Su in chow for 3 weeks.
- Assessed NADPH oxidase activity and reactive oxygen species (ROS) levels using chemiluminescence and dihydroethidium (DHE) staining.
- Quantified expression of NADPH oxidase isoforms (NOX1, NOX2, NOX4), antioxidant enzymes, and nitric oxide synthase isoforms (eNOS, iNOS) via immunofluorescence, immunoblotting, and RT-qPCR.
Main Results:
- Sunitinib treatment significantly increased NADPH oxidase activity and expression in rat retinas and eyecups.
- Elevated levels of NADPH oxidase isoforms (NOX1, NOX2, NOX4) were observed.
- Reduced nitric oxide (NO) levels and eNOS expression, alongside increased iNOS expression, were noted.
- Glutathione peroxidase levels decreased, while glutathione reductase and superoxide dismutase levels increased in Su-exposed rats.
Conclusions:
- Sunitinib treatment induces oxidative stress in the eye, primarily mediated by the NADPH oxidase system.
- Long-term Sunitinib therapy may pose a risk of retinotoxicity, potentially leading to ocular pathologies.
- Close monitoring of patients undergoing long-term Sunitinib treatment is crucial to prevent sight-threatening complications.
