Antitumorigenic effect of combination treatment with ONC201 and TRAIL in endometrial cancer in vitro and in vivo
| Autor: | Aakash Jhaveri, David T. Dicker, Jocelyn E. Ray, Marie D. Ralff, Eric A. Ross, Lanlan Zhou, Wafik S. El-Deiry |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Programmed cell death Pyridines Cell Antineoplastic Agents Heterocyclic Compounds 4 or More Rings TNF-Related Apoptosis-Inducing Ligand Mice In vivo Cell Line Tumor death receptors medicine Animals Humans Viability assay trail Pharmacology business.industry Endometrial cancer apoptosis Imidazoles ONC201 Cancer medicine.disease Endometrial Neoplasms Receptors TNF-Related Apoptosis-Inducing Ligand Pyrimidines medicine.anatomical_structure Oncology Apoptosis Cell culture endometrial cancer Cancer research Molecular Medicine Female business Research Article Research Paper |
| Zdroj: | Cancer Biology & Therapy article-version (VoR) Version of Record |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2021.1977067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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