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dc.contributor.authorBalic, Aen_US
dc.contributor.authorSørensen, MDen_US
dc.contributor.authorTrabulo, SMen_US
dc.contributor.authorSainz, Ben_US
dc.contributor.authorCioffi, Men_US
dc.contributor.authorVieira, CRen_US
dc.contributor.authorMiranda-Lorenzo, Ien_US
dc.contributor.authorHidalgo, Men_US
dc.contributor.authorKleeff, Jen_US
dc.contributor.authorErkan, Men_US
dc.contributor.authorHeeschen, Cen_US
dc.date.accessioned2015-12-09T10:53:03Z
dc.date.available2014-04-21en_US
dc.date.issued2014-07en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/9679
dc.description.abstractPancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer.en_US
dc.format.extent1758 - 1771en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofMol Cancer Theren_US
dc.subjectAnimalsen_US
dc.subjectAutophagyen_US
dc.subjectCarcinoma, Pancreatic Ductalen_US
dc.subjectCell Movementen_US
dc.subjectCell Proliferationen_US
dc.subjectChloroquineen_US
dc.subjectHedgehog Proteinsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectNeoplastic Stem Cellsen_US
dc.subjectPancreatic Neoplasmsen_US
dc.subjectRandom Allocationen_US
dc.subjectReceptors, CXCR4en_US
dc.subjectSignal Transductionen_US
dc.subjectTransfectionen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.titleChloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling.en_US
dc.typeArticle
dc.identifier.doi10.1158/1535-7163.MCT-13-0948en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/24785258en_US
pubs.issue7en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume13en_US


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