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

• Published in: Breast cancer research and treatment 2003-03, Vol.78 (1), p.17-27
• Main Authors: LEUSCHNER, Carola, ENRIGHT, Frederick M, GAWRONSKA, Barbara, HANSEL, William
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; Breast cancer; Cancer research; Cancer therapies; Cell Membrane - drug effects; Cell Membrane - pathology; Chemotherapy; Chorionic Gonadotropin, beta Subunit, Human - analogs & derivatives; Chorionic Gonadotropin, beta Subunit, Human - pharmacology; Female; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - pharmacology; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - physiopathology; Medical sciences; Melitten - analogs & derivatives; Melitten - pharmacology; Mice; Mice, Nude; Models, Animal; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - physiopathology; Pharmacology. Drug treatments; Signal Transduction - drug effects; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1023/A:1022169525521

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.