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.

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

“…However, increased TUNEL-staining was observed in ovaries of mice treated with [DLys6]GnRH-4EBP1-WT peptide. Another study that evaluated a GnRH-conjugated membrane-disrupting peptide in a breast cancer xenograft model likewise noted some death of ovarian granulosa cells (37).…”

Inhibition of Tumor Growth and Elimination of Multiple Metastases in Human Prostate and Breast Xenografts by Systemic Inoculation of a Host Defense–Like Lytic Peptide

“…In that regard, host defense-derived cytolytic cationic polypeptides, which were initially discovered due to their role in clearance of bacteria ( for reviews, see refs. [4][5][6][7], seem to overcome these limitations via a yet unknown non-receptormediated mechanism (8)(9)(10)(11)(12)(13).…”

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

“…These peptides have a central role in the innate immunity of all of the organisms, including insects, amphibians, and mammals (18). Examples include human defensins (19 -21), cecropins (22), cecropin-magainin hybrids (23,24), magainins (14), peptides conjugated to homing domains (15)(16)(17), propeptides (25), and others (26,27). These peptides preferentially bind and disrupt negatively charged phospholipid membranes, the major component of the bacterial cytoplasmic membrane.…”