Original Research ARTICLE
Digitoxin inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer
- 1Silver Pharmaceuticals LLC, United States
- 2Department of Biomedical Engineering, College of Engineering, University of Kentucky, United States
- 3University of Notre Dame, United States
- 4Department of Psychology, McGill University, Canada
- 5Uniformed Services University of the Health Sciences, United States
Castration Resistant Prostate Cancer (CRPC) is thought to be driven by a collaborative mechanism between TNF/NFB and TGFsignaling, leading to inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis. Initially, TGFis a tumor suppressor, but in advanced metastatic disease it switches to being a tumor promoter. TGFBR2 may play a critical role in this collaboration, as its expression is driven by NFB and it is the primary receptor for TGF. We have previously reported that the cardenolide drug digitoxin blocks TNF/NFB-driven proinflammatory signaling. We therefore hypothesized that digitoxin might break the collaborative process between NFB and TGF by also inhibiting expression of TGFBR2. We therefore tested whether TGF-driven EMT and resulting metastases would be suppressed. Here we show, in vitro, that digitoxin inhibits NFB-driven TGFBR2 expression, as well as Vimentin and SNAI1 expression, while E-cadherin expression is elevated. In vivo, in a syngeneic, immune competent rat model of metastatic CRPC, we show that digitoxin also suppresses Tgfbr2 expression, as well as expression of other genes classically driven by NFkB, and of multiple EMT genes associated with metastasis. Concurrently, digitoxin suppresses tumor growth and metastasis in these animals, and prolongs survival. Gross tumor recurrence following tumor resection also appears prevented in ca 30% of cases. While the existence of a collaboration between NFB and TGFto drive EMT and metastasis has previously been appreciated, we show here, for the first time, that chronic, low concentrations of digitoxin are able to block CRPC tumor progression, EMT and the ensuing metastatic disease.
Keywords: TGFBR2, , NFkappab, Prostate, Cancer, hereditary
Received: 10 Feb 2019;
Accepted: 26 Jun 2019.
Edited by:Massimo Broggini, Istituto Di Ricerche Farmacologiche Mario Negri, Italy
Reviewed by:Braden C. McFarland, University of Alabama at Birmingham, United States
Michel Rigaud, IRST
Copyright: © 2019 Pollard, Suckow, Wolter, Starr, Eidelman, Dalgard, Kumar, Battacharyya, Biswas, Yang and Pollard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Harvey Pollard, Uniformed Services University of the Health Sciences, Bethesda, 20814, Maryland, United States, Harvey.firstname.lastname@example.org