Phosphodiesterase 5 Inhibitor Sildenafil Inhibits HPV + Cervical Cancer Cells and Cervical Cancer Stem Cells by Apoptotic Induction and Telomerase Activity Modulation

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Background/Aim: Cervical cancer mortality has since long been associated with HPV positivity. However, emerging evidence points to the significant role of cancer stem cells (CSCs) in tumorigenesis, metastasis, relapse, and chemoresistance. This necessitates targeting strategies not only against HPV+ cervical cancer cells but also against CSCs. Selective phosphodiesterase type 5 inhibitors are well-known as examples of successful drug repurposing. In a small screen, previous research identified cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE) inhibition as a potential strategy for targeting cancer stem cell maintenance and survival in various cell lines. Hence, herein we studied the status of cGMP-PDE and its modulation in cervical cancer. Materials and Methods: The expression of phosphodiesterase isoforms in HPV+ (HeLa and SiHa) and HPV− (C33A) cervical cancer cell lines was studied to identify cancer-enhanced PDE isoforms. The efficacy of the corresponding PDE isoform inhibitor sildenafil was evaluated through an MTT assay and functional assays, including colony formation, cell migration, cell cycle analysis, apoptosis, DNA laddering, and telomerase activity assessment. Additionally, cAMP and cGMP levels were analyzed upon sildenafil treatment, and cervical cancer spheroids were examined using a live-dead cell assay. Results: cGMP-dependent PDE5 was identified as a cervical cancer-enhanced isoform that is modulated effectively by sildenafil. Sildenafil increased cGMP levels, induced cytotoxicity in HPV+ cell lines by cell cycle arrest, enhanced apoptosis and reduced telomerase activity. It also significantly induced apoptosis in cervical cancer spheroids. The expression of CSC markers such as ALDH1, Oct4, and SOX2 was suppressed in HPV+ cervical cancer cell lines in the presence of sildenafil. Furthermore, sildenafil inhibited wound healing and modulated epithelial-mesenchymal transition markers in cervical cancer cell lines. Conclusion: The PDE5 inhibitor sildenafil might be repurposed to be a possible therapeutic option for treating cervical cancer. Its efficacy extends to both HPV-positivity and CSCs, addressing a significant portion of cervical cancer cases.

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