CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

  • Molecules. 2019 Dec 4;24(24):4445. doi: 10.3390/molecules24244445.
Btissame El Hassouni  1 ,  Giulia Mantini  1 ,  Benoît Immordino  1 ,  Godefridus J Peters  1  2 ,  Elisa Giovannetti  1  3
Affiliations
  • 1. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands.
  • 2. Department of Biochemistry, Medical University of Gdansk, 80-210 Gdańsk, Poland.
  • 3. Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, 56017 Pisa, Italy.
PMID: 31817270 DOI: 10.3390/molecules24244445
Abstract

Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of Cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted.

Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic Cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence.

Results: CX-5461 inhibits pancreatic Cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X.

Conclusion: This study demonstrated that CX-5461 is active against pancreatic Cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.

Keywords
CX-5461; DNA damage; PDAC; Pol I.
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