Antitumorigenic effect of combination treatment with ONC201 and TRAIL in endometrial cancer in vitro and in vivo.
Cancer Biol Ther
; 22(10-12): 554-563, 2021 12 02.
Article
in En
| MEDLINE
| ID: mdl-34696710
ABSTRACT
ONC201 demonstrated promising activity in patients with advanced endometrial cancer in a Phase I clinical trial. ONC201 activates the integrated stress response (ISR) and upregulates TRAIL and its receptor DR5. We hypothesized ONC201 upregulation of DR5 could sensitize tumors to TRAIL and combination of ONC201 and TRAIL would lead to enhanced cell death in endometrial cancer models. Five endometrial cancer cell lines AN3CA, HEC1A, Ishikawa, RL952, and KLE as well as a murine xenograft model were treated with ONC201 alone or in combination with TRAIL. ONC201 decreased the cell viability of all five endometrial cancer cell lines at clinically achievable low micro-molar concentrations (2-4 µM). ONC201 activated the ISR and induced protein expression of TRAIL and DR5 at the cell surface. Pretreatment with ONC201 sensitized endometrial cancer cell lines to TRAIL, leading to increased cell death induction compared to either agent alone. Tumor growth was reduced in vivo by the ONC201/TRAIL combination treatment in the xenograft model of endometrial cancer (p = .014). Mice treated with combination treatment survived significantly longer than mice from the three control groups (p = .018). ONC201 decreased cell viability in endometrial cancer cells lines primarily through growth arrest while the combination of ONC201 and TRAIL promoted cell death in vitro and in vivo. Our results suggest a novel cancer therapeutic strategy that can be further investigated in the clinic.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Endometrial Neoplasms
/
Antineoplastic Agents
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Biol Ther
Journal subject:
NEOPLASIAS
/
TERAPEUTICA
Year:
2021
Document type:
Article
Affiliation country:
United States