1. The anti-tumour activity of DNA methylation inhibitor 5-aza-2′-deoxycytidine is enhanced by the common analgesic paracetamol through induction of oxidative stress
- Author
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Hannah J. Gleneadie, Alfredo A. Molinolo, Deena M.A. Gendoo, Yao Jiang, Amy H. Baker, Jennifer L. Bryant, Sally Roberts, Paloma Garcia, Megan Burley, Joanna L Parish, J. Silvio Gutkind, Hisham Mehanna, Ben A. Scheven, Malgorzata Wiench, Nikolaos Batis, Farhat L. Khanim, Paul R. Cooper, and Samuel J.H. Clokie
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Epigenetic therapies ,AA, arachidonic acid ,HNSCC, head and neck squamous cell carcinoma ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,DRI, dose reduction index ,Superoxides ,GSH, glutathione ,NAPQI, N-acetyl p-benzquinone-imine ,TXNRD, thioredoxin reductase ,LOX, lipoxygenase ,PTGS2, prostaglandin-endoperoxidase synthase 2 ,ERV, endogenous retrovirus ,Cell Differentiation ,Drug Synergism ,Oncology ,Head and Neck Neoplasms ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Deoxycytidine ,AML, acute myeloid leukaemia ,medicine.drug ,COX-2, cyclooxygenase 2 ,Antimetabolites, Antineoplastic ,DNA damage ,Decitabine ,HL-60 Cells ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,ROS, reactive oxygen species ,Cell Line, Tumor ,PGE2, prostaglandin E2 ,medicine ,Animals ,Humans ,DAC, 5-aza-2′-deoxycytidine ,Acetaminophen ,Cell Proliferation ,CMAP, Connectivity Map ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,CI, combination index ,Head and neck squamous cell carcinoma ,medicine.disease ,Xenograft Model Antitumor Assays ,Head and neck squamous-cell carcinoma ,Demethylating agent ,Oxidative Stress ,030104 developmental biology ,chemistry ,Cancer cell ,Cancer research ,NAC, N-acetyl-cysteine ,TXN, thioredoxin ,Reactive Oxygen Species ,business ,Oxidative stress - 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., Highlights • Paracetamol works in synergy with DAC (decitabine) to reduce cancer cell viability. • The synergistic effect is specific for decitabine and not observed for 5-azacitidine. • Paracetamol allows for DAC dose reduction without inducing DNA damage. • Paracetamol counteracts DAC-triggered activation of COX-2-PGE2 pathway. • In the presence of paracetamol DAC induces mimicry of paracetamol overdose leading to oxidative stress.
- Published
- 2021