Current Cancer Drug Targets 2017 June 23 [Epub ahead of print] [Link]

Zanellato I, Colangelo D, Osella D


Malignant pleural mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance-associated c-Myc and Fra-1. We investigated if JQ1 could enhance the efficacy of cisplatin against MPM. The antiproliferative activity of cisplatin in combination with JQ1 was assessed on MPM cell lines representative of the cellular phenotypes of this tumor (epithelioid, sarcomatoid and biphasic), and on one cisplatin-resistant sub-line (established in our laboratory). The combination schedule was optimized adopting a 3D-spheroid model. Drug combinations effects were correlated with cell cycle distribution and senescence-associated β-galactosidase positive cells. The expression of c-Myc and Fra-1 proteins was assessed by immunoblotting. DNA damage and repair was evaluated by means of alkaline comet assay. Finally, expression of some markers involved in cell cycle arrest, DNA damage, and apoptosis induction were assayed by real time quantitative PCR. JQ1 in combination with cisplatin elicits additive or synergistic (superadditive) antiproliferative effects on MPM cells due to increased senescence and apoptosis, along with c-Myc repression. JQ1 enhances the DNA damage response (DDR) even in less proficient MPM cells.