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

Anticancer Drugs. 2012 Aug;23(7):691-7. doi: 10.1097/CAD.0b013e3283514cc1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / drug effects
  • Actins / metabolism
  • Amidines / therapeutic use
  • Antineoplastic Agents / therapeutic use*
  • Benzene Derivatives / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Migration Inhibition / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chemotaxis / drug effects*
  • Epidermal Growth Factor / metabolism*
  • Humans
  • Neoplasm Metastasis / prevention & control
  • Protein Kinase C / antagonists & inhibitors*

Substances

  • Actins
  • Amidines
  • Antineoplastic Agents
  • Benzene Derivatives
  • J-4 compound
  • Epidermal Growth Factor
  • protein kinase C zeta
  • Protein Kinase C