Abstract
Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21WAF1 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.
Highlights
Ovarian cancer is the fifth leading cause of cancerrelated female deaths and was reported to be responsible for approximately 152,000 deaths worldwide in 2012 [1]
A sulforhodamine-B (SRB) assay was used to investigate growth inhibition by Nutlin-3/RG7388 or rucaparib for a panel of wild-type and mutant TP53 ovarian cancer cell lines derived from tumors of different histological subtypes [19,20,21,22] (Figure 1 and Table 1)
The GI50 values, required concentration of each compound leading to 50% growth inhibition, showed that wild-type TP53 ovarian cancer cell lines were significantly more sensitive to Nutlin-3/RG7388 compared to mutant, which is consistent with their mechanism of action (p
Summary
Ovarian cancer is the fifth leading cause of cancerrelated female deaths and was reported to be responsible for approximately 152,000 deaths worldwide in 2012 [1]. The tumor cells with BRCA1/2 mutation or other HRR defective status cannot efficiently repair these double-strand breaks, leading to cell death [6,7,8] Another mode of action for PARP inhibitors is to trap PARP proteins at the sites of DNA damage, which is highly toxic to cells due to blockade of DNA replication and induction of a replication stress www.impactjournals.com/oncotarget response. Rucaparib is one of a series of tricyclic benzimidazole carboxamide PARP inhibitors with a Ki of 1.4 nM for PARP1 in a cell-free assay It is a poly(ADP-ribose) polymerase (PARP) inhibitor successfully granted a license by the FDA and indicated as a monotherapy for the treatment of patients with a deleterious BRCA mutation (germline and/ or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
