Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications

Abstract

In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs.

Keywords: anticancer peptides; antimicrobial peptides; antitumor peptides; cationic peptides; host defense peptides.

Figure 1. Main structural classes of cationic antimicrobial peptides (AMPs)

Figure 2. Common antitumor mechanisms of cationic AMPs classified as ACPs

ACPs (anticancer peptides), or cationic AMPs with anticancer properties, selectively recognize cancer cells by electrostatic interactions with negatively charged phospholipids on the surface of eukaryotic cells [e.g., PS (phosphatidylserine)]. Some ACPs demonstrate in vivo efficacy (e.g., *MGB2, Gomesin, K6L9, LTX-315); ACPs tend to kill cancer cells by membrane perturbation (blue/cyan), although some (e.g., KLA, Pardaxin) may penetrate the target cell and disrupt the mitochondrial membrane resulting in apoptosis (green/purple). (How?), mechanism unclear; brown perpendicular bar, inhibition; CTL, cytotoxic T-Lymphocytes; M, mitochondria, SER, smooth endoplasmic reticulum; RER, rough endoplasmic reticulum; R, ribosomes; N, nucleus; V, vacuole; L, lysosome; only cholesterol and other lipids are shown; membrane proteins are omitted for clarity.

Figure 3. Helical wheel analysis of the engineered AMP K6L9 designed by Papo et al. [57]

The peptide was modeled to form an idealized amphipathic helix with only two amino acids; a structural optimization strategy that has been shown to enhance antimicrobial functions, now applied to antitumor properties as well. Arrow indicates direction of the hydrophobic moment. Structural motifs: yellow, hydrophobic; blue, cationic.

Figure 4. Strategy to improve the PK properties of AMPs adapted from Kelly et al., 2016 [183]

The AMP P18 is amidated at the C-terminus. In addition, it is covalently bound to the protease cathepsin B-sensitive linker for the release of the cancer-active drug; this linker is also covalently attached to a polyethylene glycol (PEG) polymer, which is a hydrophilic moiety that serves as a protective shield from protease degradation and drug clearance.