Host Defense Peptides and Cancer; Perspectives on Research Design and Outcomes

: Antimicrobial peptides (AMP) inhibit the proliferation of bacteria and frequently protect experimental animals from bacterial challenge. If the mode of action is membrane disintegration, one would expect that AMP can also kill cancer cells whose membrane structure lies between those of normal and bacterial cells. However, an ever-increasing number of reports suggest that AMP, with their newer name, host-defense peptides (HDP), do not directly kill bacteria under in vitro conditions when small molecule antibacterials are bactericidal. The micromolar activity may be suitable for biochemical studies but does not warrant oncology drug development. Nevertheless, as HDP are also documented to act on intracellular targets, the alternative modes of action revive the belief that antiproliferative efficacy can be obtained, indeed supported by a few successful animal efficacy studies. In addition, the passive transport properties of AMP/HDP can be utilized in the intracellular delivery of unrelated cancer drugs. Unfortunately the inherent pro-inflammatory activities of many native and designer HDP lead to oncogenic rather than anti-cancer activities in vitro and in vivo. A critical evaluation of the role of HDP in tumor development with pharmaceutically relevant animal efficacy and toxicity studies are needed before human clinical trials can be designed and initiated.