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Title:
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Antioxidants impair anti-tumoral effects of Vorinostat, but not anti-neoplastic effects of Vorinostat and caspase-8 downregulation
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Author:
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Bergadà Bertran, Laura; Yeramian Hakim, Andree; Sorolla Bardají, Anabel; Matias-Guiu, Xavier; Dolcet Roca, Xavier
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Notes:
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We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination
with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study,
we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that
reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat
induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic
mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line
Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat,
increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so
that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral
activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants
blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of
Vorinostat plus caspase-8 inhibition. |
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Rights:
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cc-by, (c) Bergadà et al., 2014
http://creativecommons.org/licenses/by/3.0/es/
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Document type:
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article
publishedVersion |
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Published by:
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Public Library of Science
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