Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1
Abstract Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients tr...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-5250-4 |
| _version_ | 1818521561290768384 |
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| author | Tahira Baloch Vanessa M. López-Ozuna Qiong Wang Emad Matanis Roy Kessous Liron Kogan Amber Yasmeen Walter H. Gotlieb |
| author_facet | Tahira Baloch Vanessa M. López-Ozuna Qiong Wang Emad Matanis Roy Kessous Liron Kogan Amber Yasmeen Walter H. Gotlieb |
| author_sort | Tahira Baloch |
| collection | DOAJ |
| description | Abstract Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial. Methods BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot. Results Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines. Conclusion Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi. |
| first_indexed | 2024-12-11T01:52:42Z |
| format | Article |
| id | doaj.art-bf195635ae86487e97a9e04aa1074178 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-11T01:52:42Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-bf195635ae86487e97a9e04aa10741782022-12-22T01:24:42ZengBMCBMC Cancer1471-24072019-01-011911910.1186/s12885-018-5250-4Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1Tahira Baloch0Vanessa M. López-Ozuna1Qiong Wang2Emad Matanis3Roy Kessous4Liron Kogan5Amber Yasmeen6Walter H. Gotlieb7Segal Cancer Center, Lady Davis Institute of Medical Research, McGill UniversitySegal Cancer Center, Lady Davis Institute of Medical Research, McGill UniversitySegal Cancer Center, Lady Davis Institute of Medical Research, McGill UniversitySegal Cancer Center, Lady Davis Institute of Medical Research, McGill UniversityDivision of Gynecologic Oncology, Jewish General Hospital, McGill UniversityDivision of Gynecologic Oncology, Jewish General Hospital, McGill UniversityDivision of Gynecologic Oncology, Jewish General Hospital, McGill UniversityDivision of Gynecologic Oncology, Jewish General Hospital, McGill UniversityAbstract Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial. Methods BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot. Results Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines. Conclusion Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi.http://link.springer.com/article/10.1186/s12885-018-5250-4Ovarian CancerBRCA1/2PARP inhibitorChemoresistanceDNA repair pathwaySynthetic lethality |
| spellingShingle | Tahira Baloch Vanessa M. López-Ozuna Qiong Wang Emad Matanis Roy Kessous Liron Kogan Amber Yasmeen Walter H. Gotlieb Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 BMC Cancer Ovarian Cancer BRCA1/2 PARP inhibitor Chemoresistance DNA repair pathway Synthetic lethality |
| title | Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 |
| title_full | Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 |
| title_fullStr | Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 |
| title_full_unstemmed | Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 |
| title_short | Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1 |
| title_sort | sequential therapeutic targeting of ovarian cancer harboring dysfunctional brca1 |
| topic | Ovarian Cancer BRCA1/2 PARP inhibitor Chemoresistance DNA repair pathway Synthetic lethality |
| url | http://link.springer.com/article/10.1186/s12885-018-5250-4 |
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