Can Peptides Kill Cancer?

Australian researchers think so.

By Klaus D Linse

A research group in Melbourne Australia designed a peptide analogue derived from a Myxoma Virus protein that showed cytotoxicity towards mouse melanoma cells (Istivan et al., 2011; Almansour et al., 2012). Will this finding allow the design of skin creams to treat skin cancer in the near future? Time will tell.

The research group used the resonant recognition model (RRM), which is a physico-mathematical model that interprets protein sequence linear information using digital signal processing methods, for the design of the cytotoxic peptide. A linear 18 amino acid long peptide was designed and its cellular cytotoxic effects were confirmed using confocal immunofluorescence microscopy. The technique allowed the researchers to measure the levels of cytoplasmic lactate dehydrogenase released into cell culture supernatants to detect apoptosis in the studied cell cultures.  Furthermore, the researchers used additional tests to detect and measure cellular cytotoxicity and cellular viability after peptide treatment. They report that the peptide analogue showed cytotoxicity towards mammalian cancer cell lines and that these results may open up new routes for the design of cancer killing peptides.  The goal is to design peptides that are toxic to melanoma cells but leave normal skin cell unaffected.

In recent years many studies showed that cationic antimicrobial peptides are toxic to bacteria but also exhibit a broad spectrum of cytotoxicity against cancer cells. The innate immune system of human skin contains antimicrobial peptides. These are skin-antimicrobial peptides known as cathelicidins (LL-37) and β-defensins. These peptides accumulate in skin affected by inflammatory diseases such as psoriasis. Cathelicidin related peptides are a family of antimicrobial polypeptides found in lysosomes of macrophages and polymorphonuclear leukocytes. Cathelicidins participate in mammalian innate immune defense against invasive bacterial infection. Defensins are a family of small cationic, antibiotic peptides that contain six cysteines in disulfide bridges. The peptides are abundant in phagocytes and small intestinal mucosa of humans and other mammals as well as in the hemolymph of insects. These peptides are part of the host defense against microbes and are thought to participate in tissue inflammation and endocrine regulation during infection. Furthermore, there is increasing evidence that antimicrobial peptides are differentially regulated in cancers. Recent research indicates that antimicrobial peptides influence the growth of tumor cells and exhibit direct cytotoxic activity towards cancer cells. They may function as a tumor suppressor agents or activate adaptive immunity suggesting that a dysregulation of antimicrobial peptides in humans may be associated with the development of cancer.

How do antimicrobial and cytotoxic peptides work?

Most antibiotic peptides function by binding to the microbial cell membrane, and, after being embedded, forming pore-like membrane defects. These pores allow the leakage of essential ions and nutrients out of the cell and thereby killing the microbes. A similar mechanism has been reported for mellitin, the principal active component of bee venom. Mellitin is a powerful stimulator of phospholipase A2. The peptide is a 26mer with the sequence GIGAVLKVLTTGLPALISWIKRKRQQ.

Possible models how the mechanism works are shown as next.

Pore forming model 1 Defensin pore model  Mellitin pore model

Models of the potential mechanism how antimicrobial peptides induce membrane permeability by disrupting and/or translocating the cell membrane.

According to the model cationic linear antimicrobial peptides bind to the negatively charged membrane surface at low concentration forming amphipatic a-helices oriented parallel to the membrane. As the concentration of the peptides increase the peptides are pulled towards and into the membrane by electrostatic attraction and the transmembranic bioelectric filed. The accumulation of the peptides is straining the membrane and the peptide arrangement results in the formation of pores.  In the case of mellitin the perpendicular orientation of the peptide leads to membrane insertion and pore formation, whereas the parallel orientation is inactive and prevents other melittin molecules from forming pores (Source: Hoskin and Ramamoorthy 2008; Ganz 2003; Bogaart et al., 2008). Not all AMPs can actually insert into and disrupt the membrane or form pores. Some peptides are too short to span the bilayer. The exact mechanism how it works for defensin peptides has not yet been worked out.

In conclusion, antimicrobial peptides appear to have the potential to allow for the development of peptide based cytotoxic therapeutic drugs. However, more studies are needed to show the suitability and safety of these types of drugs useful for oncolytic therapies.


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Categories: peptides, Synthesis

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