241 Small Molecule Inhibitors Xmd8-92 and Pv1019 Inhibit Pancreatic Tumor Xenograft Growth via a DCLK1 Dependent Mechanism

摘要: Background: XMD8-92 is a small molecule inhibitor of BMK1/MAPK7 kinase activity, key member the MAP cascade, which plays an important role in transmitting oncogenic signals tumorigenesis. Treatment with has been reported to inhibit breast and ovarian cancer cell proliferation tumor xenograft growth. It also shown that binds DCLK1 (formerly known as DCAMKL-1). Recently, CHK2 (checkpoint kinase) inhibitors have proposed chemotherapeutic agents combination cytotoxic agents. PV1019, potent selective resulted human colorectal growth inhibition. The putative intestinal pancreatic stem Tuft marker upregulated pancreatic, esophageal, colon cancers. Knockdown siRNA results inhibition several oncogenes pluripotency factors, including c-Myc, via microRNA related mechanisms. Aim: To determine whether these regulate by inhibiting DCLK1. Methods: AsPC-1, derived xenografts generated NOD/SCID mice were injected intraperitoneally (50 mg/Kg body weight) PV1019 (10 mg/Kg). siRNA-targeting encapsulated poly(lactide-co-glycolide) (PLGA)-based nanoparticles (NP-siDCLK1) directly into was used positive control. Total RNAs isolated from cells above experiments subjected realtime RT-PCR for mRNA analyses DCLK1, KRAS, Notch1, EMT, factors CDC25c (downstream target kinase). Protein carried out Western blot immunohistochemistry. Results: XMD8-92, NPsiDCLK1 treatment AsPC-1 arrest. NP-siDCLK1 treated tumors demonstrated statistically significant downregulation (~50%) its downstream targets ZEB1, ZEB2, Snail, Slug, OCT4, SOX2, LIN28, Nanog, KLF4 CDC25c. We obtained similar vitro following NP-siDCLK1. Conclusions: These data taken together demonstrate like may function. Furthermore, strengthen notion potential central regulatory protein, effective approach treating solid cancers cancer.