Targeted proapoptotic LHRH-BH3 peptide.
OBJECTIVE
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.
Dharap
Sonia S
SS
Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, USA.
Minko
Tamara
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D017931:DNA Primers; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D007987:Gonadotropin-Releasing Hormone; D020169:Caspases