| Autor: |
Gleneadie, Hannah J., Baker, Amy H., Batis, Nikolaos, Bryant, Jennifer, Jiang, Yao, Clokie, Samuel J.H., Mehanna, Hisham, Garcia, Paloma, Gendoo, Deena M.A., Roberts, Sally, Molinolo, Alfredo A., Gutkind, J. Silvio, Scheven, Ben A., Cooper, Paul R., Khanim, Farhat L., Wiench, Malgorzata |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| DOI: |
10.1101/2020.03.31.017947 |
| Popis: |
The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) 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 common analgesic paracetamol can augment the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC treatment 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 leads to glutathione depletion and ROS accumulation. Finally, this oxidative stress is further enhanced by DAC suppressing anti-oxidant and thioredoxin responses. Analyses of TCGA datasets show that the DAC/paracetamol combination targets pathways of clinical importance in many cancers. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines and corroborated in a HNSCC xenograft mouse model. In summary, paracetamol increases DAC efficacy such that it could be used at clinically relevant doses; providing a strong rationale for consideration in cancer therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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