کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2112629 | 1084405 | 2014 | 11 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism](/preview/png/2112629.png)
• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor survival rate.
• Doublecortin-like kinase1 (DCLK1) is upregulated in PDAC.
• We report XMD8-92, a DCLK1-kinase inhibitor, is effective against PDAC.
• XMD8-92 inhibits DCLK1 and regulates DCLK1 downstream tumor suppressor microRNAs.
• XMD8-92 inhibits PDAC growth, EMT, pluripotency, and angiogenesis via DCLK1.
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.
Journal: Cancer Letters - Volume 351, Issue 1, 28 August 2014, Pages 151–161