Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors.

João Lobo,Rui Henrique,Daniel Nettersheim,Rita Guimarães,Vera Miranda-Gonçalves,Daniela Barros-Silva,Friedemann Honecker,Catarina Guimarães-Teixeira,Mariana Cantante,Carmen Jerónimo,Leendert H J Looijenga,Isaac Braga,Joaquina Maurício,Vânia Camilo,Christoph Oing

doi:10.3390/cancers12102903

Abstract

Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.

Highlights

Testicular germ cell tumors (TGCTs) are among the most common solid cancers in young-adultCaucasian men, and the incidence is rising due to several environmental factors
HDACs Are Differentially Expressed among TGCT Patient Samples, Including Those Exposed to Cisplatin: In Silico Analyses and Validation
We first explored the expression of the several HDACs among the 156 TGCT tumor samples of the The Cancer Genome Atlas (TCGA) database

Summary

Introduction

The incidence is rising due to several environmental factors. These tumors are closely related to developmental biology, which constitutes the basis of their classification [1,2]. Type II TGCTs are the most common and the most clinically challenging, due to malignant behavior. They are histologically classified into seminomas (SEs) or the heterogeneous family of non-seminomas (NSs), the latter including embryonal carcinoma (EC), choriocarcinoma (CH), yolk sac tumor (YST), and teratoma (TE) subtypes, as well as mixed tumors (comprising mixtures of several components) [3]. There is a proportion of patients displaying/developing cisplatin resistance, eventually succumbing to the disease in a few months [8]; again, novel biomarkers are needed to identify upfront which patients will have or develop resistance and, very importantly, there is an urgent need for new therapies for these patients since no validated effective treatment options are available [9]

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