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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Digitoxin Inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer

Bette S Pollard1, Mark A Suckow2, William R Wolter2

  • 1Silver Pharmaceuticals, Rockville, MD, United States.

Frontiers in Oncology
|August 21, 2019
PubMed

Insights

Digitoxin blocks the collaboration between TNFα/NFκB and TGFβ signaling pathways, inhibiting tumor progression and metastasis in Castration Resistant Prostate Cancer (CRPC). This drug suppresses key genes involved in inflammation and epithelial-to-mesenchymal transition (EMT).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Castration-Resistant Prostate Cancer (CRPC) progression involves a collaboration between TNFα/NFκB and TGFβ signaling, driving inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis.
  • TGFβ signaling shifts from tumor suppression to promotion in advanced metastatic disease, with TGFBR2 potentially mediating the collaboration due to NFκB-driven expression.
  • Previous work showed digitoxin inhibits TNFα/NFκB-driven proinflammatory signaling.

Purpose of the Study:

  • To test the hypothesis that digitoxin inhibits the collaborative process between NFκB and TGFβ signaling by inhibiting TGFBR2 expression.
  • To evaluate the efficacy of digitoxin in suppressing TGFβ-driven EMT and subsequent metastases in CRPC.

Main Methods:

  • In vitro experiments assessed digitoxin's effects on NFκB-driven TGFBR2 expression, Vimentin, E-cadherin, HSPB1 mRNA, and the HSPB1/RBFOX2 mRNA ratio in PC3 cells.
  • In vivo studies utilized a syngeneic, immune-competent rat model of metastatic CRPC to evaluate digitoxin's impact on Tgfbr2, NFκB-driven genes, and EMT genes.
  • Tumor growth, metastasis, recurrence, and survival were monitored in the animal model.

Main Results:

  • In vitro, digitoxin inhibited NFκB-driven TGFBR2 expression, Vimentin, HSPB1 mRNA, and the HSPB1/RBFOX2 mRNA ratio, while increasing E-cadherin.
  • In vivo, digitoxin suppressed Tgfbr2, NFκB-driven genes, and EMT-associated metastasis genes, leading to reduced tumor growth and metastasis.
  • Digitoxin treatment prolonged survival and appeared to prevent gross tumor recurrence in approximately 30% of cases.

Conclusions:

  • Digitoxin effectively blocks the collaborative signaling between NFκB and TGFβ that drives CRPC progression, EMT, and metastasis.
  • Chronic, low-dose digitoxin administration demonstrates significant potential in inhibiting CRPC tumor progression and metastatic disease.
  • This study provides the first evidence that digitoxin can block CRPC progression and associated EMT and metastasis.
Keywords:
HSPB1NFκBTGFBR2TGFβdigitoxinhereditaryprostate cancer

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