GSE110045
Generic drug screen identifies paracetamol as 5-aza-2'-deoxycytidine sensitizer in head and neck squamous cell carcinoma cells
Aberrant DNA methylation (5mC) is one of the key characteristics of many cancers including head and neck squamous cell carcinoma (HNSCC). The DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) has anti-cancer therapeutic potential, but its clinical efficacy is currently hindered by dose-limiting side effects. Here we investigated the potential use of DAC in the treatment of HNSCC and show that its efficacy is primarily dependent on the ability of DAC to demethylate DNA. In order to establish whether HNSCC cells can be sensitized to DAC, a panel of 100 generic drugs were screened in combination with DAC. While the 100-drug panel did not sensitise DAC-resistant HNSCC cell lines to DAC treatment, the screen identified that paracetamol (acetaminophen), valproic acid and zinc acetate significantly enhanced DAC efficacy in the DAC-responsive cell lines. DAC and paracetamol were established to work in synergy, allowing DAC to be used at therapeutically relevant low doses (below 500nM). The mechanisms underlying the DAC-paracetamol synergy are multifactorial and encompass both effects of DAC on paracetamol action (alterations in the cyclooxygenase (COX) pathway and mimicry of paracetamol overdose) as well as decreased DNA methylation by paracetamol.   Therefore, we propose DAC to be a potential therapeutic in a subset of HNSCC patients with its efficacy significantly increased by use of the common analgesic paracetamol. The DAC-paracetamol synergy should also be considered in cancers with an approved DAC treatment regime. Overall design: There are four RNA-seq samples. VU40T squamous cell cacrcinoma cells were treated for 96h with 500nM 5-aza-2'-deoxycytidine (DAC), 132.3µM Paracetamol (Para), or both and compared to the untreated cells (control). For each sample three biological replicates were pooled for each RNA-seq library.