In vitro and in vivo effects of lutein against cisplatin-induced ototoxicity
Introduction
Cisplatin is a commonly prescribed platinum-based drug used to treat various types of solid tumors (testicular and ovarian carcinoma, squamous head and neck carcinoma, advanced bladder cancer, lung carcinoma, malignant gliomas and metastatic cancers such as melanoma, mesothelioma, prostate and breast cancer). Severe side effects such as ototoxicity, nephrotoxicity, myelotoxicity and gastrointestinal toxicity have been reported due to cisplatin treatment. Although nephrotoxicity can be diminished or controlled with hydration therapy, ototoxicity still poses a limitation to effective cisplatin chemotherapy (McKeage, 1995).
There is a great interest in developing effective strategies to protect the inner ear without compromising the antitumoral activity of cisplatin. Unfortunately, no therapy is currently approved for clinical use. Histologically, cisplatin causes cell death by apoptosis through different intracellular pathways. One of them is the overproduction of reactive oxygen species (ROS). This increase of ROS activate the cell compensation mechanisms, releasing glutathione enzymes and antioxidant substances. Antioxidant system depletion leads to cell apoptosis. Many experimental studies have attempted to evaluate different substances against ROS overload and other cell signaling systems at an early stage to stop the apoptotic pathways. There is a clear rationale behind the testing of antioxidants against cisplatin ototoxicity as the overload of ROS after cisplatin administration has been shown to be one of the main mechanisms triggering death pathways inside auditory sensory cells (Casares et al., 2012).
Lutein is part of the xanthophylls chemical group. It is the second carotenoid most frequently found in human serum (Khachik et al., 1997), and it is present in foods such as corn, papaya, dairy, cereal, citrus fruits and green leafy vegetables such as spinach and kale (Sommerburg et al., 1998). The molecular structure of lutein has two hydroxyl groups, one at each end of the molecule, essential for its biological action as an antioxidant (Johnson, 2002, Winkler et al., 1999). There have been many studies on the benefits of lutein in humans due to its antioxidant properties. Most of them deal with the potential protective action of lutein in eye diseases (Landrum and Bone, 2001, Beatty et al., 1999, Duncan et al., 2002), and also in heart (Howard et al., 1996, Krieglstein and Granger, 2001, Martin et al., 2000) and skin diseases (Alves Rodrigues and Shao, 2004, Britton, 1995, Krinsky, 2002, Dreher and Maibach, 2001). Recent studies suggest a protective effect against neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (Min and Min, 2014, Nataraj et al., 2015).
Up to the date there are no reports evaluating the effect of lutein on the inner ear. Due to the common characteristics between the inner ear and the retina, the antioxidant property of lutein, and the role of ROS overload in cisplatin ototoxicity, we hypothesized that lutein might play a role as a protective agent against cisplatin ototoxicity.
The aim of the present study was to evaluate the potential protective effect of lutein against cisplatin-initiated damage to the cochlea both in vitro and in vivo.
Section snippets
Chemicals
Cisplatin (1 mg/mL) was purchased from Accord Healthcare (Barcelona, Spain).
Lutein (Xanthophyll from Marigold) was purchased from Sigma–Aldrich (Sigma–Aldrich; St. Louis, USA). Lutein is a very lipophilic carotenoid, so it was diluted in 0.5% DMSO in a phosphate buffered saline solution (PBS, Sigma–Aldrich, Germany) and different dilutions were prepared from stock solution.
DMSO (Dimethyl sulfoxide) (0.5%) was purchased from Sigma–Aldrich (Sigma–Aldrich; St. Louis, USA).
Cell culture
The House Ear
Toxicity assays
Cell cultures treated with lutein alone showed no significant cell damage or cell loss (Fig. 1A). A clear dose effect was observed. Low carotenoid concentration did not affect cell viability, but exposure to concentrations of 60 and 80 μM produced a significant reduction on cell viability (81% and 84% respectively).
The HEI-OC1 cell line treated with cisplatin showed statistically significant cell damage (Fig. 1B). Changes to the pro-apoptotic nuclei were observed after Hoechst 33258 staining.
Discussion
In this study, we evaluated dose-dependent effects of lutein on HEI-OC1 cell line challenged with cisplatin. Lutein shows a dose-dependent cytoprotective effect in vitro. A protective effect was found in an in vivo animal model of cisplatin ototoxicity (albino Wistar rat), without reaching statistical significance.
Although a great diversity of pharmacological strategies have been explored to protect cochlear structures against cisplatin effects without interfering with its antitumoral activity,
Conclusions
To the best of our knowledge, the present paper is the first study to evaluate the effect of intratympanic lutein administration in vitro and in vivo. Although lutein achieved otoprotection in HEI-OC1 cells challenged with cisplatin, the present study did not show any protective effect against cisplatin toxicity in an in vivo model Wistar rat with the dose and the administration route employed.
Conflict of interest
No potencial conflicts of interest have to be disclaimed.
Acknowledgements
Research supported by a Spanish FIS GrantEI 11/00742.
The authors wish to thank Dr. Federico Kalinec (House Ear Institute, Los Angeles, CA) for the HEI-OC1 cell line facilitation, Isabel Millan for the statistical analysis, and Jaume Ponce Taylor and Alejandro Kurtz for assisting with the English language.
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