The molecular mechanisms of a novel multi-kinase inhibitor ZLJ33 in suppressing pancreatic cancer growth

Yan Li; Ke Tang; Lijing Zhang; Chao Li; Fei Niu; Wanqi Zhou; Hanze Yang; Zhiqiang Feng; Xiaoguang Chen

doi:10.1016/j.canlet.2014.09.040

The molecular mechanisms of a novel multi-kinase inhibitor ZLJ33 in suppressing pancreatic cancer growth

Cancer Lett. 2015 Jan 28;356(2 Pt B):392-403. doi: 10.1016/j.canlet.2014.09.040. Epub 2014 Oct 7.

Authors

Yan Li¹, Ke Tang¹, Lijing Zhang², Chao Li¹, Fei Niu¹, Wanqi Zhou¹, Hanze Yang¹, Zhiqiang Feng³, Xiaoguang Chen⁴

Affiliations

¹ State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
³ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: fengzhq@imm.ac.cn.
⁴ State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: chxg@imm.ac.cn.

PMID: 25301453
DOI: 10.1016/j.canlet.2014.09.040

Abstract

ZLJ33, an oral active multi-kinase inhibitor, was evaluated both in vitro and in vivo against human pancreatic cancer. It could effectively inhibit cell proliferation, induce apoptosis, and cause inhibition of invasion in pancreatic cancer cells. At a dose of 15.0 mg/kg, ZLJ33 induced tumor shrink in Mia-PaCa2, Capan2, and AsPC-1 xenografts models by 60.59%, 74.19%, and 71.54% according to the tumor weight, respectively. The effect of ZLJ33 on pancreatic cancer was mainly mediated by inactivation of p-PDGFRβ, p-c-Raf, and p-RET. Treatment with ZLJ33 did not cause side effect of hematology indexes in the pancreatic cancer xenograft model. ZLJ33 could be a potential therapeutic agent against pancreatic cancer.

Keywords: Antiproliferation; Multi-kinase inhibitor; PDGFRβ; Pancreatic cancer; RET; c-Raf.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Cell Movement / drug effects*
Cell Proliferation / drug effects*
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Humans
Hydrazines / pharmacology*
Immunoprecipitation
Mice
Mice, Inbred BALB C
Mice, Nude
Niacinamide / analogs & derivatives
Niacinamide / pharmacology
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Phenylurea Compounds / pharmacology*
Proliferating Cell Nuclear Antigen / metabolism
Protein Kinase Inhibitors / pharmacology*
Sorafenib
Tumor Cells, Cultured
Tumor Stem Cell Assay
beta Catenin / metabolism

Substances

Hydrazines
Phenylurea Compounds
Proliferating Cell Nuclear Antigen
Protein Kinase Inhibitors
ZLJ33 compound
beta Catenin
Niacinamide
Sorafenib
Extracellular Signal-Regulated MAP Kinases