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Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma.

Authors
  • Liu, Shi-He1
  • Yu, Juehua2
  • Creeden, Justin F3
  • Sutton, Jeffrey M4
  • Markowiak, Stephen4
  • Sanchez, Robbi2
  • Nemunaitis, John5
  • Kalinoski, Andrea4
  • Zhang, Jian-Ting6
  • Damoiseaux, Robert7
  • Erhardt, Paul8
  • Brunicardi, F Charles3
  • 1 Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA. Electronic address: [email protected]
  • 2 Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • 3 Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  • 4 Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  • 5 Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  • 6 Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  • 7 Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • 8 Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, USA.
Type
Published Article
Journal
Cancer letters
Publication Date
Aug 21, 2020
Volume
491
Pages
97–107
Identifiers
DOI: 10.1016/j.canlet.2020.08.002
PMID: 32829010
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity. Copyright © 2020 Elsevier B.V. All rights reserved.

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