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.
Keywords: Alternative mode of action, apoptosis, cell proliferation, half-inhibitory concentration, necrosis, oncogene, surface
negative charge, tumor model.
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