Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo.
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.
Leuschner
Carola
C
Pennington Biomedical Research Center, Agricultural Experiment Station, LSU, Baton Rouge, LA 70808-4124, USA. Leuschc@pbrc.edu
Enright
Frederick M
FM
Gawronska
Barbara
B
Hansel
William
W
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000473:pathology; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D008555:Melitten / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018997:Chorionic Gonadotropin, beta Subunit, Human; C098827:hecate 1; D008555:Melitten; D007987:Gonadotropin-Releasing Hormone