Title:JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells
Volume: 18
Issue: 8
Author(s): Ilaria Zanellato*, Donato Colangelo and Domenico Osella
Affiliation:
- Dipartimento di Scienze ed Innovazione Tecnologica (DiSIT), Università del Piemonte Orientale, viale Teresa Michel 11, 15121 Alessandria,Italy
Keywords:
Malignant mesothelioma, BET bromodomain inhibition, JQ1, epigenetics, platinum-based chemotherapy, c-Myc,
Fra-1.
Abstract: Background: 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.
Objective: We investigated if JQ1 could enhance the efficacy of cisplatin against MPM.
Methods: 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. The combination schedule was optimized adopting a 3Dspheroid
model. Drug combination effects were correlated with cell cycle distribution and senescence-
associated β-galactosidase positive cells. The expression of c-Myc and Fra-1 proteins and
some apoptosis markers was assessed by immunoblotting and RT-qPCR. DNA damage and repair
were evaluated by means of alkaline comet assay.
Results: JQ1 in combination with cisplatin elicited additive or synergistic (superadditive) antiproliferative
effects on MPM cells, depending on the cell line. The combination showed tumor regression
on the 3D-spheroid model. It induced increased apoptosis, along with decreased c-Myc and, sometimes,
Fra-1 expression. JQ1 decreased cisplatin-induced DNA breaks in all MPM cells and increased
senescence even in less proficient cells, thus enhancing the DNA Damage Response (DDR).
Conclusion: The superadditive effect is due to c-Myc repression. The consequent DDR enhancement
triggers to apoptosis induction and/or permanent growth arrest (senescence), depending on the
MPM cellular context, leading to tumor regression. Thus, the pharmacological modulation of BET
activity could represent a promising tool for future MPM therapy.
