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Translational Cancer Mechanisms and Therapy

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

Sakthivel Muniyan, Satyanarayana Rachagani, Seema Parte, Sushanta Halder, Parthasarathy Seshacharyulu, Prakash Kshirsagar, Jawed A. Siddiqui, Raghupathy Vengoji, Sanchita Rauth, Ridwan Islam, Kavita Mallya, Kaustubh Datta, Lei Xi, Anindita Das, Benjamin A. Teply, Rakesh C. Kukreja and Surinder K. Batra
Sakthivel Muniyan
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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  • ORCID record for Sakthivel Muniyan
  • For correspondence: sbatra@unmc.edu s.muniyan@unmc.edu
Satyanarayana Rachagani
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Seema Parte
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Sushanta Halder
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Parthasarathy Seshacharyulu
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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  • ORCID record for Parthasarathy Seshacharyulu
Prakash Kshirsagar
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Jawed A. Siddiqui
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Raghupathy Vengoji
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Sanchita Rauth
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Ridwan Islam
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Kavita Mallya
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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Kaustubh Datta
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
2Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
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Lei Xi
3Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia.
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Anindita Das
3Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia.
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Benjamin A. Teply
2Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
4Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
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Rakesh C. Kukreja
3Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia.
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Surinder K. Batra
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
2Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
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  • For correspondence: sbatra@unmc.edu s.muniyan@unmc.edu
DOI: 10.1158/1078-0432.CCR-20-1569 Published November 2020
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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 chemotherapy-induced side-effects among patients with advanced prostate cancer.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5720–34

  • Received April 24, 2020.
  • Revision received July 22, 2020.
  • Accepted August 17, 2020.
  • Published first August 26, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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Sildenafil Potentiates the Therapeutic Efficacy of Docetaxel in Advanced Prostate Cancer by Stimulating NO-cGMP Signaling
Sakthivel Muniyan, Satyanarayana Rachagani, Seema Parte, Sushanta Halder, Parthasarathy Seshacharyulu, Prakash Kshirsagar, Jawed A. Siddiqui, Raghupathy Vengoji, Sanchita Rauth, Ridwan Islam, Kavita Mallya, Kaustubh Datta, Lei Xi, Anindita Das, Benjamin A. Teply, Rakesh C. Kukreja and Surinder K. Batra
Clin Cancer Res November 1 2020 (26) (21) 5720-5734; DOI: 10.1158/1078-0432.CCR-20-1569

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Sildenafil Potentiates the Therapeutic Efficacy of Docetaxel in Advanced Prostate Cancer by Stimulating NO-cGMP Signaling
Sakthivel Muniyan, Satyanarayana Rachagani, Seema Parte, Sushanta Halder, Parthasarathy Seshacharyulu, Prakash Kshirsagar, Jawed A. Siddiqui, Raghupathy Vengoji, Sanchita Rauth, Ridwan Islam, Kavita Mallya, Kaustubh Datta, Lei Xi, Anindita Das, Benjamin A. Teply, Rakesh C. Kukreja and Surinder K. Batra
Clin Cancer Res November 1 2020 (26) (21) 5720-5734; DOI: 10.1158/1078-0432.CCR-20-1569
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