TY - JOUR
T1 - Sildenafil potentiates the therapeutic efficacy of docetaxel in advanced prostate cancer by stimulating NO-cGMP signaling
AU - Muniyan, Sakthivel
AU - Rachagani, Satyanarayana
AU - Parte, Seema
AU - Halder, Sushanta
AU - Seshacharyulu, Parthasarathy
AU - Kshirsagar, Prakash
AU - Siddiqui, Jawed A.
AU - Vengoji, Raghupathy
AU - Rauth, Sanchita
AU - Islam, Ridwan
AU - Mallya, Kavita
AU - Datta, Kaustubh
AU - Xi, Lei
AU - Das, Anindita
AU - Teply, Benjamin A.
AU - Kukreja, Rakesh C.
AU - Batra, Surinder K.
N1 - Funding Information:
The authors thank Dr. Jessica Mercer for her editorial contributions. The authors also acknowledge the University of Nebraska Medical Center (UNMC) Flow Cytometry Research Facility and Tissue Sciences Facility (TSF) for their resources and services. This work and the authors are, in part, supported by the NIH grant U01 CA185148 (to S.K. Batra); R01 CA221813, DK120866, HL118808 (to R.C. Kukreja) and R01 HL134366 (to R.C. Kukreja and A. Das), and Department of Defense Award W81XWH-18-1-0308 (PC170891; to S.K. Batra and R.C. Kukreja).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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 chemotherapy-induced side-effects among patients with advanced prostate cancer.
AB - 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 chemotherapy-induced side-effects among patients with advanced prostate cancer.
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U2 - 10.1158/1078-0432.CCR-20-1569
DO - 10.1158/1078-0432.CCR-20-1569
M3 - Article
C2 - 32847934
AN - SCOPUS:85100825022
SN - 1078-0432
VL - 26
SP - 5720
EP - 5734
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -