Synergistic antiproliferative and pro-apoptic effects of epigenetic drugs guadecitabine and domatinostat in p,leural mesothelioma cells

PURPOSE: Pleural mesothelioma (PM) is a rare and highly aggressive cancer of the serosal cavities with about 2,500/year new cases diagnosed in the United States. PM is a fatal cancer, with a 5-yrs survival rate of 12%. PM can be distinguished in three main histological subtypes, i.e., epithelioid, biphasic and sarcomatoid. PM tumour is highly resistant to radio-/chemo-therapies, and current therapies are ineffective. DNA methylation impairment alongside the dysregulation of histone deacetylases (HDACs) are frequent in PM, making epigenetic-based antitumor therapies feasible approaches. Guadecitabine (gDAC) and domatinostat are two novel antitumor agents whose efficacy have been demonstrated previously in cancer. This study aimed to evaluate the efficacy of combined epigenetic-based antitumor agents gDAC and domatinostat in the PM epithelioid cell line MPP89, with particular focus on the synergistic effects on proliferation and apoptosis. METHODS: The potential synergistic efficacy of combined gDAC and domatinostat treatment on MPP89 cells’ proliferation was tested by WST-1 assay and analyzed using Synergyfinder 2.0 tool. Apoptosis was studied by evaluating the expression of 84 apoptotic-associated genes using RT2 Profiler PCR mRNA array. The potential anti-proliferative efficacy of single treatment with gDAC and domatinostat was evaluated in epithelioid IST-MES2, sarcomatoid, PPM-Mill, and biphasic, MSTO-211H, PM cells and in two control cell lines, i.e., lung fibroblast cells MRC-5 and human mesothelial cells HMC. RESULTS: Combination treatment with gDAC and domatinostat induced a strong synergistic effect in inhibiting cell proliferation and inducing apoptosis in MPP89. Gene expression analysis revealed a strong positive modulation of pro-apoptotic genes in MPP89 cells treated with the combination of gDAC and domatinostat, compared to either agent alone or untreated cells. Moreover, domatinostat treatment led to a significant reduction in cell proliferation of MPP89, IST-MES2, PPM-Mill and MSTO- 211H at low doses. Furthermore, MPP89 cells resulted to be sensitive to gDAC treatment. No significant effects have been determined in the domatinostat-treated MRC-5 and HMC control cell lines. CONCLUSIONS: In conclusion, the combination treatment of gDAC and domatinostat at low and clinically well tolerated doses exhibited a synergistic activity in inducing anti-proliferative and pro-apoptotic effects in PM cell line MPP89. Further research is needed to validate our in vitro findings in vivo and explore the mechanisms underlying the synergistic effects of domatinostat and gDAC in PM cells. CLINICAL IMPLICATIONS: This study contributes to addressing the urgent need for novel therapeutic approaches in PM and suggests the potential clinical utility of gDAC and domatinostat combination treatment in PM patients.