Ovarian cancer (OC) is the leading cause of gynecologic cancer-related deaths due to late diagnosis and chemoresistance. RNA-seq data, conducted in collaboration with our group, compared the expression of transcription levels between normal Fallopian tube and high-grade serous ovarian carcinoma samples and revealed phosphodiesterase 7-A as a novel potential therapeutic target against the disease. Metabolic cell viability assays (MCV) were conducted following OC cells treatment with selective PDE7 inhibitor (BRL50481) in monotherapy or in association with paclitaxel (PTX). Mechanism of action of the drug was evaluated by cell cycle analysis, anexina V/PI assay, immunoblotting, real-time PCR and scanning/transmission electron microscopy. Data showed that the use of the BRL50481 in monotherapy reduced A2780 cells MCV by ~60% in a dose-dependent manner after 48h treatment, but nothing significant was observed in OVCAR3. On the other hand, the association of BRL50481 and PTX promoted inhibition of MCV in both cell lines analyzed. An increase in the potency of PTX was also observed, an aspect verified with the reduction of its IC50 in relation to monotherapy by 30% (p<0.01). Treatment chronology in cell survival was also verified. Thus, pretreatment of A2780 with BRL50481 200μM followed by its association with PTX promoted a reduction in cells MCV of ~70% (p<0.01) compared to treatment with PTX alone. With regard to OVCAR3, 400μM pretreatment of BRL50481 provided a VCM reduction of ~20% (p<0.001). Therefore, our results showed beneficial effect between the combination of PDE7 inhibitor and PTX, which allowed reduction of the PTX concentration used in A2780 and OVCAR3 by ~82.7 x 108 and 80.4 x 103uM, respectively. Moreover, the combination of BRL50481 and PTX promoted increased cell necrosis in OVCAR3. In addition, pretreatment of OVCAR3 with BRL50481 modulated the gene expression of the cytokines, as well as increased IL-6 secretion. The combination of BRL50481 and PTX further modulated negatively the PI3K/AKT/mTOR signaling pathway in both cell lines studied. Furthermore, the A2780-pretreated cells showed an increase in the expression of the pro-apoptotic Bax protein. Still, cell death may be related to the induction of autophagy seen in both by the increase of the expression of beclin. Moreover, BRL50481 promoted changes in OC cellular morphology, resembling the induction of cell death by BRL50481, as well as mitochondria and mitochondrial cristae modification. The association of the PDE7 inhibitor with PTX has been proved potentially beneficial in the fight against OC. The impressive additive effect between the drugs allows us to postulate a substantial decrease in PTX neurotoxicity caused in patients by the drug. Our current challenge is to synthesize less toxic BRL50481 analogues, which is only approved for experimental purposes, hence providing hope for better life quality to OC patients.
Citation Format: Nayara G. Tessarollo, Isabella S. Guimarães, Diandra Z. dos Santos, Taciane B. Henriques, Marcele LM Souza, Laura Maciel, João Carlos A. Almeida, Alan Branco, Ian V. Silva, Leticia BA Rangel. Phosphodiesterase 7-A is a novel potential therapeutic target against ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5883.