324P - All-<italic>trans</italic> retinoic acid sensitizes ovarian cancer to niraparib by inhibiting ALDH1A1 activity

Background

Poly (ADP-ribose) polymerase inhibitors (PARPi) used for maintenance therapy of patients with epithelial ovarian cancer (EOC) will eventually develop resistance. Increased expressions of ALDH1A1 and PARP1 during platinum-based chemotherapy contribute to the resistance of EOC to PARPi. All-trans retinoic acid (ATRA) has been shown to be an inhibitor of ALDH1A1 activity. We investigated whether ATRA could circumvent ALDH1A1-mediated resistance of EOC cells to Niraparib.

Methods

EOC A2780, OVCAR3 and ID8 cells were pre-treated with cisplatin for 6h, and then incubated with Niraparib or combined with ATRA for 48h. The expression of PARP1 was detected by RT-qPCR and Western Blot (WB); the inhibition of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay; the Annexin V-FITC/PI, active caspase 3 and cleaved-PARP1 for apoptosis were assayed by flow cytometry and WB, respectively; the IC₅₀ value for Niraparib or combined with ATRA was detected by crystal violet assay; In vivo, A2780 and ID8 were implanted in female BALB/c nude and C57BL/6JGpt mice, respectively. Tumor-bearing mice were treated with four cycles of cisplatin (5mg/kg, i.p) twice a week followed by maintenance treatment with Niraparib (50 mg/kg, i.g) or combined with ATRA (0.6 mg/kg, i.p) once a day for 21 days. The volume and weight of tumor, and survival of mice were observed.

Results

All EOC cells treated with cisplatin showed higher ALDH1A1, PARP1, ALDH1A1 activity, and IC₅₀ values for Niraparib than their parental cells, suggesting that cisplatin could lead to propagation of Niraparib resistance of EOC cells due to increased expression of ALDH1A1 and PARP1. ATRA was found to significantly (P<0.01) reduce ALDH1A1 activity and the IC₅₀ for Niraparib, and to induce active caspase 3 and cleaved-PARP1 for apoptosis; the tumor growth was inhibited by 64.5% and 45.2%, and the median survival of tumor-bearing mice for A2780 and ID8 were extended up to 10.5 and 12.7 weeks, respectively after treatment of Niraparib combined with ATRA, compared to those of Niraparib (P< 0.01).

Conclusions

Our findings suggest that ATRA combined with Niraparib prevents increased ALDH1A1 activity-mediated resistance and improve the survival outcome for maintenance therapy of EOC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.