XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism

Cancer Lett. 2014 Aug 28;351(1):151-61. doi: 10.1016/j.canlet.2014.05.011. Epub 2014 May 28.

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.

Keywords: Angiogenic factors; DCLK1; Epithelial–mesenchymal transition; Pluripotency factors; XMD8-92.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzodiazepinones / pharmacology*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Gene Expression / drug effects
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Benzodiazepinones
  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • LIN28B protein, human
  • MIRN200 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptor, Notch1
  • XMD 8-92
  • mirnlet7 microRNA, human
  • DCLK1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins