title: XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism.
abstract: XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC.
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States.
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States.
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.affiliation: COARE Biotechnology Inc., Oklahoma City, OK 73104, United States.
authors.forename: Eddie
authors.initials: E
authors.lastname: Bannerman-Menson
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States.
authors.forename: Naushad
authors.initials: N
authors.lastname: Ali
authors.affiliation: COARE Biotechnology Inc., Oklahoma City, OK 73104, United States.
authors.forename: Panayotis
authors.initials: P
authors.lastname: Pantazis
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States. Electronic address: courtney-houchen@ouhsc.edu.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000089742:Doublecortin-Like Kinases; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D047908:Intracellular Signaling Peptides and Proteins; C000715467:KLF4 protein, human; C117307:KRAS protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C516326:LIN28B protein, human; C533896:MIRN200 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; C568790:XMD 8-92; C487931:mirnlet7 microRNA, human; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Angiogenic factors; DCLK1; Epithelial–mesenchymal transition; Pluripotency factors; XMD8-92