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

Abstract

Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D-and L-amino acids (diastereomer), which targets both androgen-independent and androgendependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all L-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.

Relative Spatial Positions of Tryptophan and Cationic Residues in Helical Membrane-active Peptides Determine Their Cytotoxicity

“…In addition, intratumoral administration of a cationic anticancer peptide in animal models has resulted in a long term, specific cellular immunity against the treated tumor (16). Papo et al (17,18) have demonstrated that enzymatically stable cationic peptides with a high specificity for cancer cells versus normal cells inhibit tumor growth in animal models after intravenous injections. Thus, these peptides confer a promising novel strategy for developing new anticancer agents that may overcome some of the obstacles in cancer therapy (for reviews, see Refs.…”

An amphipathic lytic peptide for enhanced and selective delivery of ellipticine

“…We proposed a ''CLP-assisted uptake'' mechanism to explain these traits, which may also be a general reason for the previously reported synergistic effect between other CLPs and anticancer agents. 34,35 Some recent studies using CLPs, conjugating or complexing with hydrophobic anticancer drugs as drug delivery platforms, also showed selective and fast cellular uptake of drugs, which could have a similar mechanism. 26,36 This ''therapeutic drug carrier'' strategy could provide several unique benefits.…”

D-K6L9 Peptide Combination with IL-12 Inhibits the Recurrence of Tumors in Mice

“…D-K 6 L 9 is an example of cell membrane-acting peptide which triggers necrosis of cancer cells (Papo et al 2004). …”

“…Introduction of d aminoacids increases stability of this peptide in other organisms as it makes proteolysis more difficult and increases peptide selectivity (Papo et al 2004). D-K 6 L 9 features both hydrophobic aminoacids (leucine) and hydrophilic ones (lysine), which make it an amphipathic molecule.…”

“…In aqueous solutions, this peptide does not preserve an ordered secondary structure, whereas after attachment to the lipid bilayer it adopts α-helical conformation (Papo and Shai 2003). It is preferentially bound by membranes rich in negatively charged acidic phospholipids (Papo et al 2004, 2006), an augmented number of which are found in cancer cell membranes (Mader and Hoskin 2006). The peptide is bound by phosphatidylserine present in the outer membrane of the bilayer (Papo et al 2006).…”