Membrane Disrupting Lytic Peptides for Cancer Treatments

Abstract

Membrane disrupting lytic peptides are abundant in nature and serve insects, invertebrates, vertebrates and humans as defense molecules. Initially, these peptides attracted attention as antimicrobial agents; later, the sensitivity of tumor cells to lytic peptides was discovered. In the last decade intensive research has been conducted to determine how lytic peptides lyse bacteria and tumor cells. A number of synthetic peptides have been designed to optimize their antibiotic and anti-tumor properties and improve their therapeutic capabilities. The sequences of alpha-helical cationic membrane disrupting peptides has been discussed, their proposed mechanisms of action reviewed, and their roles in cell selectivity and tumor cell destruction considered. Parameters important for the selection and design of lytic peptides for cancer treatments include increased activities against tumor cells, low cytolytic activities to normal mammalian cells and erythrocytes. The conjugation of lytic peptides with hormone ligands and the production of pro-peptides provide methods for targeting of cancer cells. The therapeutic possibilities in cancer treatment by targeted lytic peptides are broad and offer improvement to currently used chemotherapeutical drugs. Lytic peptides interact with the tumor cell membrane within minutes, and their activity is independent of multi-drug resistance. Lytic peptide-chorionic gonadotropin (CG) conjugates destroy primary tumors, prevent metastases and kill dormant and metastatic tumor cells. These conjugates do not destroy vital organs; they are not antigenic, and are more toxic to tumor cells than to non-malignant cells.

A theoretical analysis of secondary structural characteristics of anticancer peptides

“…At present, the factors that determine differences in the efficacy and selectivity of ACPs are poorly understood, inhibiting the potential to develop these peptides as therapeutically useful anticancer agents [1,2]. However, it is generally accepted that net positive charge, hydrophobicity and amphiphilicity play major roles in the anticancer action of ACPs [1] and here, theoretical analyses are used to study the contribution of these physiochemical properties to the efficacy and selectivity of these peptides.…”

“…Moreover, ACP CT peptides can also show selectivity between different types of cancer cells. At present, the factors that determine these differences in efficacy and selectivity are poorly understood, limiting efforts to develop ACPs as therapeutically useful anticancer agents [1,2].…”

Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase

“…It was reported that the ability to adopt a certain amphipathic secondary structure is critical to the membrane activity of a lytic peptide (3,7,10). CD spectroscopy reveals peptide structural transition during its translocation from an aqueous environment to a hydrophobic membrane-like environment.…”

“…The ability to adopt certain amphipathic secondary structures is considered critical to the function of lytic peptides (3,7,10). Cyclization affects peptide behavior by imposing spatial restriction.…”

Use of hecate–chorionic gonadotropin β conjugate in therapy of lutenizing hormone receptor expressing gonadal somatic cell tumors

“…They serve as defense molecules against microorganisms (bacteria, fungi and viruses) especially in insects that do not possess an immune system (lymphocytes or antibodies). Despite the diversity of these peptides, they share common characteristics: positive charge, linearity, amphipathic and α-helical structure in a hydrophobic environment and rapid destruction of negatively charged membranes (Leuschner and Hansel 2004) (Figure 1). Most of these peptides are toxic to bacteria but elude normal eukaryotic cells.…”