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J-4: a novel and typical preclinical anticancer drug targeting protein kinase C ζ.

Authors
Type
Published Article
Journal
Anti-Cancer Drugs
0959-4973
Publisher
Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins
Publication Date
Volume
23
Issue
7
Pages
691–697
Identifiers
DOI: 10.1097/CAD.0b013e3283514cc1
PMID: 22430047
Source
Medline

Abstract

Metastasis is the major cause of morbidity and mortality from breast cancer. Cell motility and chemotaxis play important roles in the metastatic cascade of cancer cells. Protein kinase C ζ (PKCζ) mediates cancer cell chemotaxis by regulating cytoskeleton rearrangement and cell adhesion. In the current study, we investigated the inhibitory effect of a compound called J-4 targeting PKCζ. J-4 was tested with inhibitory concentration (IC(50)) of 10 µmol/l using a Z'-LYTE™ Kinase Assay-Ser/Thr 7 Peptide Kit. Our results show that J-4 inhibited spontaneous migration and epidermal growth factor (EGF)-induced chemotaxis of human breast cancer cell MDA-MB-231. Through an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the drug designated as J-4 had no obvious cytotoxicity in vitro. Meanwhile, in the presence of J-4, the cells showed defects in EGF-induced actin polymerization and adhesion. Furthermore, J-4 dampened EGF-induced phosphorylation and recycling of cofilin. Taken together, our data demonstrate that J-4 is a new and typical inhibitor that blocks the PKCζ pathway. Moreover, a better understanding of the mechanism of action of J-4 may provide a novel medical therapeutic strategy for cancer treatment that would block metastasis, thereby reducing the proliferation and dissemination of cancer cells and increasing patient survival.

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