Cationic amphiphilic peptides with cancer-selective toxicity

Abstract

During the last two decades cationic amphiphilic peptides and peptide sequences (CAPs) with cancer-selective toxicity have appeared. Based on their spectrum of anticancer activity CAPs can be divided into two major classes. The first class includes peptides that are highly potent against both bacteria and cancer cells, but not against mammalian cells. The second class includes peptides that are toxic to bacteria, and both mammalian cancer and non-cancer cells. Most antimicrobial and anticancer CAPs share a common membranolytic mode of action that results either in the selective disruption of the cancer cell membrane or permeation and swelling of mitochondria. The electrostatic attraction between the negatively charged membrane components of bacterial and cancer cells and CAPs is believed to play a crucial role in the disruption of bacterial and cancer cell membranes. This mode of action appears to bypass established resistance mechanisms. However, it is currently unclear as to why some CAPs kill cancer cells when others do not. In addition, non-membranolytic mode of actions of CAPs is increasingly recognized to contribute significantly to the anticancer activity of certain CAPs. The development of CAP-based chemotherapeutics is complicated due to the traditionally poor pharmacokinetic properties and high manufacturing costs of peptides and the low intrinsic selectivity for cancer cells. Peptidomimetic approaches combined with novel selective delivery devices show promise in overcoming some of these obstacles. Furthermore, the ability of CAPs to bypass established resistance mechanisms provides an attractive strategy to develop novel lead structures for cancer treatment.