Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

Abstract

We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleukin-1-converting enzyme (FLICE)-like inhibitory protein). Co-treatment of PCa cells with sildenafil and DOX for 48 hours showed reduced expression of both long and short forms of FLIP (FLIP-L and -S) as compared to individual drug treatment. Over-expression of FLIP-s with an adenoviral vector attentuated the enhanced cell-killing effect of DOX and sildenafil. Colony formation assays also confirmed that FLIP-S over-expression inhibited the DOX and sildenafil-induced synergistic killing effect as compared to the cells infected with an empty vector. Moreover, siRNA knock-down of CD95 abolished the effect of sildenafil in enhancing DOX lethality in cells, but had no effect on cell killing after treatment with a single agent. Sildenafil co-treatment with DOX inhibited DOX-induced NF-κB activity by reducing phosphorylation of IκB and nuclear translocation of the p65 subunit, in addition to down regulation of FAP-1 (Fas associated phosphatase-1, a known inhibitor of CD95-mediated apoptosis) expression. This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer.

Single‐cell redox states analyzed by fluorescence lifetime metrics and tryptophan FRET interaction with NAD(P)H

“…Doxorubicin is one of the potent anti‐cancer drugs known to induce apoptosis. In a recent study, it was shown that doxorubicin targets OXPHOS for apoptosis induction . In the study, mitochondrial response doxorubicin treatment for 24 h in colon and prostate cancer cells showed increase in mitochondrial ROS, increase in cytochrome‐C release, increase in caspase‐3 activation and increase in the percentage of apoptotic cells.…”

Phosphodiesterase type 5 and cancers: progress and challenges

“…left ventricular dysfunction) [ 216 ]. Next, the same research group investigated the mechanism by which sildenafil may sensitize prostate cancer cell to doxorubicin-mediated apoptosis, showing CD95 (death receptor Fas)/FLIP (Fas-associated death domain FADD) as key regulators of this event [ 217 ]. In 2016, by in vitro cell culture and in vivo xenograft approaches, it was clearly demonstrated that PDE5/cGMP/PKG signal targets to Hippo/TAZ pathway in maintaining stemness of prostate cancer stem cells, evidencing a novel role of PDE5 in governing stem cell features [ 218 ].…”

Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer

“…Furthermore, several studies have demonstrated that sildenafil showed antitumor activity in mouse models 49 - 52 and that PDE5 inhibition resulted in growth inhibition of tumor cells in vitro particularly by enhancing anticancer drugs. 20 , 53 - 61 Also, sildenafil has been suggested as useful in mitigating the nephrotoxicity of cisplatin in rats. 2 …”