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Open AccessArticle

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

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
*
Author to whom correspondence should be addressed.
Academic Editors: Elisa Giovannetti and Patrizia Diana
Molecules 2019, 24(24), 4445; https://doi.org/10.3390/molecules24244445
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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