xmd-8-92 and Pancreatic-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Doublecortin-Like Kinases; Epithelial-Mesenchymal Transition; Gene Expression; Intracellular Signaling Peptides and Proteins; Kruppel-Like Factor 4; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); ras Proteins; Receptor, Notch1; RNA-Binding Proteins; RNA, Messenger; Tumor Burden; Xenograft Model Antitumor Assays