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

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

Author information

1
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.
2
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.
3
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
4
COARE Biotechnology Inc., Oklahoma City, OK 73104, United States.
5
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.
6
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, United States.
7
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.

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

PMID:
24880079
DOI:
10.1016/j.canlet.2014.05.011
[Indexed for MEDLINE]

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