Pre-Treatment with BET Inhibitors Increases the Sensitivity of Cancer Cell Lines to Cisplatin and Oxaliplatin

Platinum compounds, such as cisplatin, carboplatin and oxaliplatin are utilised widely in therapeutic strategies against a range of malignancies, for instance Neuroblastoma and Ovarian cancer. These compounds elicit anticancer effects by damaging DNA via the formation of crosslinks with nitrogenous bases, leading to DNA damage responses and the induction of apoptotic signalling. Although these compounds may produce promising initial responses, the emergence and establishment of chemoresistant tumour cells can often result in tumour relapses and treatment failure. The mechanisms driving resistance to platinum compounds are numerous, and act via a diverse range of cellular processes, such as reducing uptake of the drug, increasing DNA repair activity, and reducing apoptotic signalling.

There are also research efforts to elucidate the epigenetic modifications of resistant tumours, and the means in which these changes are recognised and transduced. The Bromodomain and Extra-Terminal domain (BET) family of proteins recognise acetylated histones, and regulate transcription via association with transcriptional co-activators and RNA polymerase II. BET family members, such as BRD4, are able to form 'super-enhancers', promoting oncogenic activity of genes such as MYC. Consequently, BET proteins have been identified as potential anticancer drug targets, prompting the development of BET inhibitors.

This study investigated whether the BET inhibitors, JQ-1 and I-BET726, were able to increase the sensitivity of parental and oxaliplatin-resistant Neuroblastoma (UKF-NB3) and cisplatin-resistant Ovarian cancer cell lines (COLO-704, EFO-21 and EFO-27) to their respective platinum compounds. BET inhibitor pre-treatments, using the IC10 and IC50 concentrations of JQ-1 and I-BET726 as single-agents for each cell line, resulted in increased sensitivity to the platinum compounds, as determined by MTT cell viability assays. Increasing the pre-treatment incubation duration from 0hrs to 24hrs and 48hrs improved the response to platinum agents, and the same effect was observed with increasing pre-treatment dosage. In summary, these results suggest that BET inhibitors are able to increase the sensitivity of cancer cells to platinum chemotherapeutics.