TY - JOUR
T1 - CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage
AU - el Hassouni, Btissame
AU - Mantini, Giulia
AU - Immordino, Benoît
AU - Peters, Godefridus J.
AU - Giovannetti, Elisa
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85076351490&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31817270
U2 - https://doi.org/10.3390/molecules24244445
DO - https://doi.org/10.3390/molecules24244445
M3 - Article
C2 - 31817270
SN - 1420-3049
VL - 24
JO - Molecules
JF - Molecules
IS - 24
ER -