Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems.
Cells
; 9(7)2020 07 10.
Article
in En
| MEDLINE
| ID: mdl-32664214
ABSTRACT
The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Glioblastoma
/
HSP90 Heat-Shock Proteins
/
Histone Deacetylase 1
/
Histone Deacetylase 2
/
Histone Deacetylase Inhibitors
/
Antineoplastic Agents
Type of study:
Etiology_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cells
Year:
2020
Document type:
Article
Affiliation country: