Efficacy of HDAC inhibitors Belinostat and Panobinostat against cisplatin-sensitive and cisplatin-resistant testicular germ cell tumors

Authors and Affiliations:

João Lobo ^1,2,3,4,*, Catarina Guimarães-Teixeira ^1,*, Daniela Barros-Silva ¹, Vera Miranda-Gonçalves ¹, Vânia Camilo ¹, Rita Guimarães ^1,2, Mariana Cantante ^1,2, Isaac Braga ⁵, Joaquina Maurício ⁶, Christoph Oing ⁷, Friedemann Honecker ⁸, Daniel Nettersheim ⁹, Leendert HJ Looijenga ⁴, Rui Henrique ^1,2,3,§,# and Carmen Jerónimo ^1,3,§,#

^{1 Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;} 

^{2 Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;}

^{3 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal}

^{4 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands;}

^{5 Department of Urology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;} 

^{6 Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;}

^{7 Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany & Laboratory of Radiation Biology and Experimental Radiation Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany;}

^{8 Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany & Tumour and Breast Center ZeTuP St. Gallen, Rorschacher Strasse 150, 9006 St. Gallen, Switzerland; Friedemann;}

^{9 Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany;} 

^{* joint first authors}

^{§ joint senior authors}

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. Because 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.

Journal: Cancers

Link: https://doi.org/10.3390/cancers12102903