Phosphodiesterase 7 (PDE7): A Potential Novel Therapeutic Target in Ovarian Cancer

Nayara Gusmão Tessarollo¹Isabella dos Santos Guimarães²Diandra Zipinotti dos Santos¹Taciane Barbosa Henriques¹Paulo Cilas Morais Lyra Junior¹Josiany Carlos De Souza¹Tatiana Massariol Pimenta³Bárbara da Silva Martins³Solenny Maria Silva Butzene³José Matheus Simões Padilha³Leide Laura Figueiredo Maciel⁴João Carlos de Aquino Almeida⁴Ian Victor Silva⁵Leticia Batista Azevedo Rangel^1,3,6*

• ¹Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espírito Santo, Vitória, Brazil
• ²Division of Clinical Research and Technological Development, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
• ³Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Brazil
• ⁴Laboratory of Physiology and Biochemistry of Microorganisms, State University of North Fluminense Darcy Ribeiro, Campos, Brazil
• ⁵Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil
• ⁶Biochemistry Program, Health Sciences Center, Federal University of Espírito Santo, Vitória, Brazil

Chemoresistance and disease relapse in epithelial ovarian cancer (EOC) highlight the need for novel therapeutic strategies. Here, we investigated phosphodiesterase 7A (PDE7A) inhibition in EOC cells based on 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. Diphenyltetrazolium bromide (MTT) assays revealed that while BRL 50481 reduced metabolic cell 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. 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. 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. Pre-treatment 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.