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

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Abstract

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 E2 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.

Bibliographic note

Funding Information: This research was supported by grants from the FP7 Framework Marie Curie Actions CIG (methDRE) to M. Wiench and The Royal Society ( RS-9-10-2012 ) to M. Wiench. H.J. Gleneadie received a joint University of Birmingham and Medical Research Council fellowship. M.B is funded by a non-clinical CRUK PhD studentship awarded to the CRUK Birmingham Centre. JP is funded by the MRC ( MR/R022011/1 and MR/T015985/1 ).

Details

Original languageEnglish
Pages (from-to)172-186
Number of pages15
JournalCancer Letters
Volume501
Early online date5 Jan 2021
Publication statusPublished - 31 Mar 2021

Keywords

  • Acetaminophen, Acute myeloid leukaemia, Decitabine, Epigenetic therapies, Head and neck squamous cell carcinoma

ASJC Scopus subject areas