XMD8-92 通过依赖于 DCLK1 的机制抑制胰腺肿瘤异种移植物生长。
XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism.
机构信息
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.
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.
出版信息
Cancer Lett. 2014 Aug 28;351(1):151-61. doi: 10.1016/j.canlet.2014.05.011. Epub 2014 May 28.
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.
XMD8-92 是一种具有抗癌活性的激酶抑制剂，可对抗肺癌和宫颈癌，但它对胰腺导管腺癌（PDAC）的作用尚不清楚。双皮质激酶 1（DCLK1）在包括 PDAC 在内的各种癌症中上调。在这项研究中，我们表明 XMD8-92 抑制 AsPC-1 癌细胞的增殖和肿瘤异种移植物的生长。XMD8-92 处理的肿瘤通过上调肿瘤抑制 miRNA let-7a、miR-144、miR-200a-c 和 miR-143/145，显著下调了 DCLK1 及其几个下游靶标（包括 c-MYC、KRAS、NOTCH1、ZEB1、ZEB2、SNAIL、SLUG、OCT4、SOX2、NANOG、KLF4、LIN28、VEGFR1 和 VEGFR2）；但它不影响 BMK1 下游基因 p21 和 p53。这些数据表明，XMD8-92 治疗导致 DCLK1 和下游致癌途径（EMT、多能性、血管生成和抗凋亡）的抑制，是一种有前途的针对 PDAC 的化疗药物。
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