Sildenafil Potentiates the Therapeutic Efficacy of Docetaxel in Advanced Prostate Cancer by Stimulating NO-cGMP Signaling

Abstract

Purpose: Docetaxel plays an indispensable role in the management of advanced prostate cancer. However, more than half of patients do not respond to docetaxel, and those good responders frequently experience significant cumulative toxicity, which limits its dose duration and intensity. Hence, a second agent that could increase the initial efficacy of docetaxel and maintain tolerability at biologically effective doses may improve outcomes for patients.Experimental Design: We determined phosphodiesterase 5 (PDE5) expression levels in human and genetically engineered mouse (GEM) prostate tissues and tumor-derived cell lines. Furthermore, we investigated the therapeutic benefits and underlying mechanism of PDE5 inhibitor sildenafil in combination with docetaxel using in vitro, Pten conditional knockout (cKO), derived tumoroid and xenograft prostate cancer models.Results: PDE5 expression was higher in both human and mouse prostate tumors and cancer cell lines compared with normal tissues/cells. In GEM prostate-derived cell lines, PDE5 expression increased from normal prostate (wild-type) epithelial cells to androgen-dependent and castrated prostate-derived cell lines. The addition of physiologically achievable concentrations of sildenafil enhanced docetaxel-induced prostate cancer cell growth inhibition and apoptosis in vitro, reduced murine 3D tumoroid growth, and in vivo tumorigenicity as compared with docetaxel alone. Furthermore, sildenafil enhanced docetaxel-induced NO and cGMP levels thereby augmenting antitumor activity.Conclusions: Our results demonstrate that sildenafil's addition could sensitize docetaxel chemotherapy in prostate cancer cells at much lesser concentration than needed for inducing cell death. Thus, the combinatorial treatment of sildenafil and docetaxel may improve anticancer efficacy and reduce chemotherapyinduced side-effects among patients with advanced prostate cancer.

The Potential Role of Sildenafil in CancerManagement Through EPR Augmentation

“…Similar results were observed in syngeneic cell lines and Pten cKO derived tumoroids where an increase in caspase-3 and PARP cleavage was detected [49]. The combination treatment demonstrated a significant decrease in tumoroid size and growth, with loss of integrity, apoptosis, condensed structure and structural blebbing [50].…”

“…The therapeutic combination significantly lowered tumor weight compared to docetaxel alone. Further exploration in the molecular pathways responsible for this phenomenon identified a lower percentage of Ki67-positive nuclei and a higher frequency of cleaved caspase-3 positive cells relative to groups treated with monotherapy, thus promoting apoptosis and tumor regression [50]. Likewise, Hsu, J.-L. et al reported the synergestic effects between vincristine and sildenafil in PC-3-derived cancer xenografts in nude mice demonstrating a decrease in tumor weight relative to the single chemotherapeutic agent [46].…”

“…Muniyan, S. et al orthotopically implanted luciferase-labelled C4-2Bcells into the dorsolateral lobe of the prostate in immunodeficient mice to investigate the therapeutic efficacy of co-administration of docetaxel and sildenafil in advanced prostate cancer [50]. The therapeutic combination significantly lowered tumor weight compared to docetaxel alone.…”

Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics

“…Nevertheless, the addition of PDE-5i as adjuvant chemotherapy sensitizing agents may work through multiple mechanisms and is not strictly limited to one class of chemotherapeutic agents. Emerging evidence suggests that the sildenafil also improved the efficacy of docetaxel at treating CRPC, which the authors hypothesized was due to improved action of docetaxel on effector pathways, namely cGMP-mediated apoptosis and ERK/JNK downregulation [280]. Although numerous preclinical studies outline the potential roles for PDE-is in anticancer therapy, clinical trials (Table 4) have only begun to show evidence of efficacy [265,281].…”

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

“…Similar results were observed in syngeneic cell lines and Pten cKO derived tumoroids where an increase in caspase-3 and PARP cleavage was detected [ 49 ]. The combination treatment demonstrated a significant decrease in tumoroid size and growth, with loss of integrity, apoptosis, condensed structure, and structural blebbing [ 50 ]. A demonstration between the 3D model translation, compared to the 2D line, further suggests an enhanced probability for in vivo studies and clinical application on patients.…”