Phosphodiesterase 5 inhibitor Sildenafil inhibits HPV + cervical cancer cells and cervical cancer stem cells by apoptotic induction and telomerase activity modulation

India contributes to 70% of cervical cancer mortality worldwide in spite of the available pap smear screening and administration of vaccine as prognosis with advanced recurrent cervical cancer is still very poor. Though cervical cancer has been linked with HPV positivity, increasing evidence suggests that cancer stem cell population (CSCs) may play an important role in cervical cancer (CC) tumorigenesis, metastasis, relapse and chemo-resistance, thus requiring potential targets which would not only affect HPV + cervical cancer cells but also cervical cancer stem cells. Selective phosphodiesterase type 5 inhibitors are well known as examples of successful drug repurposing. In a small screen, previous research identified cGMP-PDE inhibition as potential strategy to target CSC maintenance and survival in various cell lines. Hence, we were interested to study the status of cGMP-PDE in cervical cancer and the efficacy of a cGMP-specific phosphodiesterase inhibitors like PDE5 inhibitor, sildenafil on cervical cancer cells as well as cervical cancer stem cells. Amongst cGMP-PDEs and PDEs having dual specificity, expression of PDE5 was observed to increase significantly in both the HPV + cervical cancer cells (HeLa and SiHa) while PDE3 was detected only in HPV + HeLa cell line. Sildenafil elevated cGMP levels, was cytotoxic to HPV + cell lines and was effective in the modulation in telomerase activities. Sildenafil also showed significant abrogation of cervical cancer spheroids through pro-apoptotic induction regressing stemness markers like ALDH1, Oct4 and SOX2 associated with CSC phenotype in cervical cancer spheroids. Moreover, sildenafil-mediated significant regression of metastasis was observed in cervical cancer cell lines making sildenafil a possible therapeutic option for cervical cancer having efficacy against HPV positivity as well as cervical cancer stem cells which attribute to the lion-share of the cervical cancer cases.