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Phosphodiesterase 7: a potential novel therapeutic target in ovarian cancer
Nayara Gusmão Tessarollo1, Isabella Dos Santos Guimarães2, Diandra Zipinotti Dos Santos1
1Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil.
Introduction:
Chemoresistance and disease relapses in epithelial ovarian cancer (EOC) highlight the need for novel therapeutic strategies. Here, we investigated phosphodiesterase 7A (PDE7A) as a potential target in ovarian cancer treatment.
Methods:
Gene expression was performed by RNA sequencing data comparing high-grade serous ovarian carcinoma (HGSOC) and fallopian tube samples. The PDE7 inhibitor BRL 50481, alone or combined with paclitaxel (PTX), was tested in drug-sensitive A2780 and multi-resistant OVCAR3 cells by Diphenyltetrazolium bromide (MTT) assay. To validate data from the high throughput RNA-sequencing assays, RT-qPCR and Immunoblotting were performed. Cytokine expression was analyzed by RT-qPCR and the quantification was obtained by ELISA. Scanning and Transmission Electron Microscopy were also carried out.
Results And Discussion:
MTT assays revealed that while BRL 50481 reduced metabolic cellular viability (MCV) in A2780 (IC50 = 200 μM), its combination with PTX decreased MCV in both lines, reducing PTX IC50 by 103- and 625-fold in A2780 and OVCAR3, respectively. PDE7 inhibition suppressed the PI3K/AKT/mTOR pathway, upregulated the pro-apoptotic protein Bcl-2 Associated X-protein (BAX) in A2780, and increased IL-6 expression in OVCAR3. Pretreatment with BRL 50481 followed by PTX downregulated vimentin and octamer-binding transcription factor (OCT4), while inducing morphological changes and mitochondrial cristae alterations. Inhibiting PDE7 can enhance the paclitaxel-induced apoptosis by promoting mitochondrial dysfunction and suppressing survival pathways, thereby improving ovarian cancer treatment efficacy. The results need to be validated in additional in vivo models.
Insights
Targeting phosphodiesterase 7A (PDE7A) with BRL 50481 enhances paclitaxel efficacy in ovarian cancer. This combination therapy overcomes chemoresistance by promoting apoptosis and inhibiting survival pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epithelial ovarian cancer (EOC) frequently relapses due to chemoresistance, necessitating novel therapeutic targets.
- Phosphodiesterase 7A (PDE7A) is explored as a potential therapeutic target in ovarian cancer.
Purpose of the Study:
- To investigate the efficacy of inhibiting PDE7A, using BRL 50481, alone and in combination with paclitaxel (PTX), in ovarian cancer treatment.
- To elucidate the molecular mechanisms underlying PDE7A inhibition in enhancing chemotherapy response.
Main Methods:
- Gene expression analysis via RNA sequencing.
- Cell viability assays (MTT) on drug-sensitive (A2780) and resistant (OVCAR3) ovarian cancer cells.
- Validation using RT-qPCR, immunoblotting, ELISA, and electron microscopy.
Main Results:
- BRL 50481 combined with PTX significantly reduced cell viability and lowered the paclitaxel IC50 in both cell lines.
- PDE7 inhibition suppressed the PI3K/AKT/mTOR pathway and upregulated BAX, promoting apoptosis.
- Combination therapy induced morphological and mitochondrial changes, downregulating vimentin and OCT4.
Conclusions:
- Inhibiting PDE7A enhances paclitaxel-induced apoptosis in ovarian cancer by inducing mitochondrial dysfunction and suppressing survival pathways.
- PDE7A inhibition represents a promising strategy to improve the efficacy of paclitaxel in treating chemoresistant ovarian cancer.
- Further validation in in vivo models is required.
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