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Open AccessArticle

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

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands
Department of Biochemistry, Medical University of Gdansk, 80-210 Gdańsk, Poland
Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, 56017 Pisa, Italy
Author to whom correspondence should be addressed.
Academic Editors: Elisa Giovannetti and Patrizia Diana
Molecules 2019, 24(24), 4445;
Received: 12 November 2019 / Revised: 28 November 2019 / Accepted: 2 December 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Drug Resistance in Targeted Cancer Therapy)
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. View Full-Text
Keywords: CX-5461; Pol I; PDAC; DNA damage CX-5461; Pol I; PDAC; DNA damage
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El Hassouni, B.; Mantini, G.; Immordino, B.; Peters, G.J.; Giovannetti, E. CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage. Molecules 2019, 24, 4445.

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