From first glance at the first link, the answer seems to be that many cancer cells tend to have negative membrane charges, like bacteria and some viruses, but unlike healthy mammalian cells (which are neutral). So, our cationic hole puncher brilacidin can selectively kill negatively charged cancer cells (and bacteria and some viruses) while sparing healthy cells, potentially.
1.2.1. Membranes of Cancer Cells
To be useful as anti-cancer agents, cytotoxic peptides like AMPs (Fig. 1A) need to target and damage the membranes of cancer cells, sparing non-cancer cells. Important in this regard is that fact that cancer cells have significant differences in their cell membranes that favor the targeting of such cytotoxic peptides. In non-cancer cells, the total membrane charge is more neutral due to the presence of zwitterionic phospholipids like phosphatidylcholine (PC) and sphingomyelin, with phosphatidylserine (PS) and phosphotidylethanolamine (PE) located in the inner leaflet of plasma membrane [7]. Cancer cells, in contrast, lose this membrane symmetry and expose anionic PS on the outer leaflet of the plasma membrane, increasing the overall negative charge [8]. Exposure of PS is linked to the metastatic phenotype [9] and has been documented to occur with multiple cancer tissue types (reviewed in [10]). Another source for increased negative charges on the membrane of cancerous cells is the sialic acid residues linked to glycolipids and glycoproteins like mucins. Mucin 1 (Muc 1) is highly expressed in most breast carcinomas as well as in ovarian, pancreatic, and lung cancers as examples [11]. Proteoglycans with highly negatively charged side chains, heparin sulfate and chondroitin sulfate, can also contribute to changing the charge on the surface of cancer cell membranes. A number of cancers with altered proteoglycan expression and sulfonation have been documented [12, 13]. In addition to increased negative charges on the cell membranes of cancer cells, changes in membrane fluidity are associated with some cancers [14, 15] and may be linked to higher cholesterol levels [16]. Another difference is the increased surface area due to more microvilli on cancer cells compared to non-cancer cells [17]. This collective evidence indicates that significant differences between the cell membranes of cancer cells and non-cancer cells exists that could support the specific targeting and cytotoxic action of a peptide therapeutic.
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2.1. Anti-Microbial Peptides
Anti-microbial peptides (AMPs) (also called host defense peptides or cationic antimicrobial peptides) are low molecular weight molecules (~10–40 amino acids) with a cationic amphipathic structure that enables them to interact with anionic lipid membranes. Naturally occurring AMPs are part of the protective innate immune response to microbes in many species that include mammals, amphibians and insects. Because of their mode of action, in which the AMPs target membranes, AMPs could be used as alternative cancer therapeutics. In AMP databases, more than 100 AMPs have been characterized as having potential anti-tumor activity [26]. Lipid membranes are the major target of most AMPs; therefore, the development of drug resistance is less likely to occur since damaging cytotoxicity can take place within minutes of peptide introduction [27].
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Magainins, derived from the skin of the African clawed frog, Xenopus laevis, were among the first AMPs tested for anti-cancer activity [29]. Early work showed that magainin 2 formed an amphiphilic a-helical structure (Fig. 3A) that porated membranes [30] and improved the survival of animals bearing tumors [31]. Local treatment with magainin 2 in a xenograft model of tumors in nude mice, led to the ablation of the tumors [32]. Multiple lines of evidence support the cytotoxic effects of magainin 2 in melanoma, breast and lung cancers. As example, magainin 2 was highly effective inhibiting the proliferation of bladder cancer cell lines with a range of IC50 values of 31–135µM (BrdU assay), while comparable IC50 values for normal fibroblast cells lines were undetermined [33]. Additional studies demonstrated that the anti-cancer effects of magainins were selective. Lower concentrations of magainins were found to be toxic to cancer cells but not lymphocytes or fibroblasts, and magainins were resistant to serum proteolysis [34,32]. Conjugation of magainin 2 to a tumor-homing peptide, bombesin, exemplified the potential uses of the anti-tumor effects of the conjugate peptide (MG2B) [35]. Bombesin alone was not cytotoxic, while MG2B had an IC50 range of 10–15 µM in breast cancer and melanoma cell lines that was at about 10 times lower than unconjugated magainin 2 and 6–10 lower than the IC50 for normal fibroblasts [35]. The utility of magainin 2 as an anti-cancer agent is bolstered by the fact that it’s mechanism of action makes it a poor candidate for development of resistance [36].
