Preclinical Studies on the Effect of Rucaparib in Ovarian Cancer: Impact of BRCA2 Status
| Autor: | Emmanouil Karteris, Marcia Hall, Sayeh Saravi, Silvano Tosi, Zena Alizzi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Indoles
QH301-705.5 Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors Biology Article chemistry.chemical_compound PARP1 Cell Line Tumor medicine Humans Biology (General) Rucaparib PARP inhibitors PI3K/AKT/mTOR pathway BRCA2 Protein Ovarian Neoplasms Cell growth TOR Serine-Threonine Kinases BRCA mutation Wild type Recombinational DNA Repair General Medicine medicine.disease rucaparib ovarian cancer chemistry homologous recombination deficiency Mutation Cancer research Female Homologous recombination Ovarian cancer DNA Damage Signal Transduction |
| Zdroj: | Cells, Vol 10, Iss 2434, p 2434 (2021) Cells Volume 10 Issue 9 |
| ISSN: | 2073-4409 |
| Popis: | Copyright: © 2021 by the authors. Background: Approximately 50% of ovarian cancer patients harbour homologous recombination repair deficiencies. These deficiencies have been successfully targeted using poly (ADP-ribose) polymerase inhibitors (PARPi) particularly for patients harbouring BRCA1/2 mutations. The aim of this study is to assess the effects of the PARPi rucaparib in vitro using cell lines with BRCA2 mutations in comparison to those with BRCA2 wild type. Methods: Cell proliferation assays, RT-qPCR, immunofluorescence, annexin V/PI assays were used to assess the effects of rucaparib in vitro. Results: The BRCA2 mutant ovarian cancer cell line PEO1 exhibited higher PARP1 activity when treated with H2O2 compared to wild type cell lines. The migratory and proliferative capacity of PEO1 cells was compromised following treatment with rucaparib 10 µM compared to BRCA2 wild-type cell lines via a mechanism involving the mTOR pathway. Rucaparib treatment significantly increased DNA damage primarily in PEO1 cells and SKOV3 cells compared with wild type. Conclusions: Appropriate identification of robust predictive biomarkers for homologous recombination deficiency using ‘liquid’ biopsies would facilitate the identification of patients suitable for PARPi therapy. Preliminary efforts to undertake such testing are described here. This study also demonstrates the mechanisms of action of rucaparib (PARPi) which may involve elements of the mTOR pathway. Cancer Treatment & Research Trust (CTRT Charity Number 29909). |
| Databáze: | OpenAIRE |
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