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

Lajkó, Eszter and Szabó, Ildikó and Andódy, Katalin and Pungor, András and Mező, Gábor and Kőhidai, László (2013) Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH-III derivatives in Tetrahymena and human leukemia cell line. JOURNAL OF PEPTIDE SCIENCE, 19 (1). pp. 46-58. ISSN 1075-2617

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Abstract

GnRH-III has been shown to exert a cytotoxic effect on the GnRH-R positive tumor cells. The chemotactic drug targeting (CDT) repre-sents 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 threenative GnRHs (hGnRH-I, cGnRH-II, and lGnRH-III) and nine GnRH-III derivativeswere evaluated in twomodel cells (TetrahymenapyriformisandMono Mac 6humanmonocytes). According toour results, the native GnRH-III elicited the highest chemoattractant and adhesion inducer activitiesof 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 de-termine the chemotactic and adhesion modulation potency of each fragment. The application of the chemoattractant GnRH-III deri-vatives 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 candi-dates to be applied in CDT: these compounds might act both as carrier, delivery unit, and antitumor agents.

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