PDE5 inhibitors therefore offer the attractive prospect of increasing immunogenic cell death while at the same time enhancing the immune response. We

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Similarly, Booth et al. 96 have shown that Fildena synergised with celecoxib or the celecoxib derivative OSU-03012 to increase cell death of a range of glioblastoma stem-like cells. The showed that PCSCs showed expressed 2.8-fold more PDE5 than non-stem prostate cancer cells and that PDE5/cGMP/PKG signalling was a key component of PCSC-related Hippo/TAZ pathway. PDE5 over-expression in vitro was associated with an increase in cell motility and migration—which could be reversed by Fildena.

Zhu and Strada 92 summarised the increased activity of PDE isoforms in a range of colon, breast, prostate, lung and other cancer cell lines and showed that PDE5 was the most commonly over-expressed isoform. Mechanistically the addition of Fildena to doxorubicin increased ROS production in both PC-3 and DU145 cell lines though not in PrEC normal cells. A study into the potential clinical use of Fildena to address treatment sensitivity was published by Lin et al. 84 following the range of in vitro results described above.

Furthermore, in ABCG2-overexpressing cells, Fildena inhibited resistance to ABCG2 substrate anticancer drugs, for example, mitoxantrone. Shi et al. 80 , 81 showed that Fildena increased the in vitro sensitivity of ABCB1-overexpressing drug-resistant cells to colchicine, vinblastine and paclitaxel but not cisplatin. In vitro the combination treatment increased PD-L1 and ODC expression in tumour cells and enhanced the expression of MHCA and HMGB1.

Table 4. Clinical trials in cancer using PDE5 inhibitors. However, a more recent study has reported no such association 74 and a retrospective study indicated a trend towards PDE5-inhibitor mediated protective effect against primary prostate cancer 75. The authors reported an elevated risk of melanoma hazard ratio (HR), 1.92; 95% confidence interval (CI) 1.14—3.22 but no increased risk of squamous cell carcinoma or basal cell carcinoma.

Metastases of stable patients were also characterised by a significant reduction of FOXP3 T reg cells post-treatment as compared with baseline. A separate randomised controlled trial in HNSCC patients (NCT00894413) at the same institution showed that Fildena, at a dose of 20 mg/day, significantly decreased peripheral MDSC numbers and increased general immunity as measured by delayed type hypersensitivity response (P < 0.002) 62. Based on these incidental findings a small Phase II open-label clinical trial (NCT00165295) was initiated 54 Patients, (n = 30, 18 of whom were treatment naive), with slowly progressive Waldenstrom's macroglobulinemia and ineligible for active therapy were treated with 100 mg/day of Fildena, with a starting dose of 25 mg/day and escalating to the target dose over a 4 week period.

Additional ex vivo analysis showed evidence that Fildena, at a concentration of 0.01 μg/mL, caused apoptosis in lymphoplasmacytic cells from the five patients. However, Fildena enhanced the anti-proliferative effects of CNP in both cell lines compared to either single agent treatment (P < 0.05).

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