Targeted proapoptotic LHRH-BH3 peptide.

Purpose: The purpose of this work was to construct and evaluate a novel targeted proapoptotic peptide for cancer treatment.
Methods: The peptide consisted of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to LHRH receptors and a synthetic BCL-2 homology 3 (BH3) domain peptide as an apoptosis inducer and a suppressor of antiapoptotic cellular defense. Anticancer activity of the peptide was evaluated on different cancer cell lines.
Results: The targeting receptor to LHRH peptide is overexpressed in several cancer cell lines but is not expressed in healthy human visceral organs. LHRH and BH3 peptides when applied separately did not demonstrate cellular toxicity. In contrast, the LHRH-BH3 peptide was toxic in several cancer cell lines. Coincubation of LHRH and LHRH-BH3 peptides significantly decreased cytotoxicity of the latter. It was found that the LHRH-BH3 peptide induced apoptosis by simultaneous inhibition of the antiapoptotic function of BCL-2 protein family and activation of caspase-dependent signaling pathway.
Conclusions: The proposed anticancer proapoptotic LHRH-BH3 peptide simultaneously affects two molecular targets: 1) extracellular cancer-specific LHRH receptors and 2) the intracellular controlling mechanisms of apoptosis. The results of this work may be used to design novel approaches for the treatment of various cancers.