TY - JOUR
T1 - Efficacy of HDAC inhibitors belinostat and panobinostat against cisplatin-sensitive and cisplatin-resistant testicular germ cell tumors
AU - Lobo, João
AU - Guimarães-Teixeira, Catarina
AU - Barros-Silva, Daniela
AU - Miranda-Gonçalves, Vera
AU - Camilo, Vânia
AU - Guimarães, Rita
AU - Cantante, Mariana
AU - Braga, Isaac
AU - Maurício, Joaquina
AU - Oing, Christoph
AU - Honecker, Friedemann
AU - Nettersheim, Daniel
AU - Looijenga, Leendert H.J.
AU - Henrique, Rui
AU - Jerónimo, Carmen
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
KW - Belinostat
KW - Cisplatin resistance
KW - Epidrugs
KW - HDAC inhibitors
KW - Panobinostat
KW - Targeted therapies
KW - Testicular germ cell tumors
UR - http://www.scopus.com/inward/record.url?scp=85092469353&partnerID=8YFLogxK
U2 - 10.3390/cancers12102903
DO - 10.3390/cancers12102903
M3 - Article
AN - SCOPUS:85092469353
VL - 12
SP - 1
EP - 19
JO - Cancers
JF - Cancers
IS - 10
M1 - 2903
ER -