Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH-III derivatives in Tetrahymena and human leukemia cell line

J Pept Sci. 2013 Jan;19(1):46-58. doi: 10.1002/psc.2472. Epub 2012 Dec 4.

Abstract

GnRH-III has been shown to exert a cytotoxic effect on the GnRH-R positive tumor cells. The chemotactic drug targeting (CDT) represents a new way for drug delivery approach based on selective chemoattractant guided targeting. The major goal of the present work was to develop and investigate various GnRH-III derivatives as potential targeting moieties for CDT. The cell physiological effects (chemotaxis, adhesion, and signaling) induced by three native GnRHs (hGnRH-I, cGnRH-II, and lGnRH-III) and nine GnRH-III derivatives were evaluated in two model cells (Tetrahymena pyriformis and Mono Mac 6 human monocytes). According to our results, the native GnRH-III elicited the highest chemoattractant and adhesion inducer activities of all synthesized peptides in micromolar concentrations in monocytes. With respect to chemoattraction, dimeric derivatives linked by a disulfide bridge ([GnRH-III(C)](2) ) proved to be efficient in both model cells; furthermore, acetylation of the linker region ([GnRH-III(Ac-C)](2) ) could slightly improve the chemotactic and adhesion effects in monocytes. The length of the peptide and the type of N-terminal amino acid could also determine the chemotactic and adhesion modulation potency of each fragment. The application of the chemoattractant GnRH-III derivatives was accompanied by a significant activation of phosphatidylinositol 3-kinase in both model cells. In summary, our work on low-level differentiated model cells of tumors has proved that GnRH-III and some of its synthetic derivatives are promising candidates to be applied in CDT: these compounds might act both as carrier, delivery unit, and antitumor agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Adhesion*
  • Cell Line, Tumor
  • Chemotaxis*
  • Chromatography, High Pressure Liquid
  • Gonadotropin-Releasing Hormone / chemistry
  • Gonadotropin-Releasing Hormone / pharmacology*
  • Humans
  • Leukemia / pathology*
  • Molecular Sequence Data
  • Pyrrolidonecarboxylic Acid / analogs & derivatives*
  • Pyrrolidonecarboxylic Acid / chemistry
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Signal Transduction
  • Spectrometry, Mass, Electrospray Ionization
  • Tetrahymena pyriformis / metabolism*

Substances

  • gonadotropin-releasing hormone-III
  • Gonadotropin-Releasing Hormone
  • Pyrrolidonecarboxylic Acid