Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo.

Abstract

We have prepared conjugates of a membrane disrupting lytic peptide (hecate) and a 15-amino acid segment of the beta-chain of CG and hecate and the decapeptide, luteinizing hormone releasing hormone (LHRH). We have tested the concept that these conjugates will target breast cancer cells expressing LH/CG or LHRH receptors. In previous studies, we were able to destroy prostate cancers in vitro and in vivo with lytic peptide conjugates. Hecate, hecate-betaCG and LHRH-hecate were added to cultures of the human breast cancer cell lines MCF-7 and MDA-MB-435S. Hecate and its conjugates showed concentration dependent toxicity to both cell lines. The lytic peptide alone showed similar EC50 values for both cell lines; however, there was a significant difference between the EC50 values when the conjugates were tested. The hormone dependent MCF-7 cell line was less sensitive to the betaCG conjugate than to the LHRH conjugate; the reverse was found for the hormone independent MDA-MB-435S cells. Removal of steroids decreased the sensitivity of MCF-7 cells to both lytic peptide conjugates and this sensitivity could be restored by adding estradiol. Activation of protein kinase C further increased the sensitivity to the drug. MDA-MB-435S xenografts were established in intact female athymic nude mice, which were treated once a week for 3 weeks with hecate-betaCG via the lateral tail vein. The ability of hecate-betaCG to destroy xenografts of human breast cancer cells (MDA-MB-435S) in nude mice was demonstrated for the first time. We conclude that hecate-betaCG and LHRH-hecate conjugates could serve as useful drugs for the treatment of breast cancer.

• Authors: Carola Leuschner, Frederick M Enright, Barbara Gawronska, William Hansel
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 78 Issue 1 Pg. 17-27 (Mar 2003) ISSN: 0167-6806 [Print] Netherlands
• PMID: 12611453 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chorionic Gonadotropin, beta Subunit, Human
• hecate 1
• Melitten
• Gonadotropin-Releasing Hormone

Topics

• Amino Acid Sequence
• Animals
• Cell Membrane (drug effects, pathology)
• Chorionic Gonadotropin, beta Subunit, Human (analogs & derivatives, pharmacology)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacology)
• Mammary Neoplasms, Experimental (drug therapy, physiopathology)
• Melitten (analogs & derivatives, pharmacology)
• Mice
• Mice, Nude
• Models, Animal
• Neoplasms, Hormone-Dependent (drug therapy, physiopathology)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays