The anti-tumour activity of DNA methylation inhibitor 5-aza-2'-deoxycytidine is enhanced by the common analgesic paracetamol through induction of oxidative stress.

Autor: Gleneadie HJ; School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK; Present Address: MRC London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK., Baker AH; School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK., Batis N; Institute of Head and Neck Studies and Education (InHANSE), The University of Birmingham, Birmingham, B15 2TT, UK., Bryant J; Institute of Head and Neck Studies and Education (InHANSE), The University of Birmingham, Birmingham, B15 2TT, UK., Jiang Y; Institute of Clinical Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Clokie SJH; West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's Hospital, Birmingham, B15 2TG, UK., Mehanna H; Institute of Head and Neck Studies and Education (InHANSE), The University of Birmingham, Birmingham, B15 2TT, UK., Garcia P; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Gendoo DMA; Centre for Computational Biology, Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Roberts S; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Burley M; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Molinolo AA; Moores Cancer Center and Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA., Gutkind JS; Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA., Scheven BA; School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK., Cooper PR; School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK; Present Address: Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand., Parish JL; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Khanim FL; Institute of Clinical Sciences, The University of Birmingham, Birmingham, B15 2TT, UK., Wiench M; School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: m.d.wiench@bham.ac.uk.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2021 Mar 31; Vol. 501, pp. 172-186. Date of Electronic Publication: 2021 Jan 05.
DOI: 10.1016/j.canlet.2020.12.029
Abstrakt: The DNA demethylating agent 5-aza-2'-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC specifically upregulates cyclooxygenase-2-prostaglandin E 2 pathway, inadvertently providing cancer cells with survival potential, while the addition of paracetamol offsets this effect. Secondly, in the presence of paracetamol, DAC treatment leads to glutathione depletion and finally to accumulation of ROS and/or mitochondrial superoxide, both of which have the potential to restrict tumour growth. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines, further corroborated in a HNSCC xenograft mouse model and through mining of publicly available DAC and paracetamol responses. The sensitizing effect of paracetamol supplementation is specific to DAC but not its analogue 5-azacitidine. In summary, the addition of paracetamol could allow for DAC dose reduction, widening its clinical usability and providing a strong rationale for consideration in cancer therapy.
(Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: