Indole-3-acetic acids and horseradish peroxidase: A new prodrug/enzyme combination for targeted cancer therapy

The radical-cations formed on one-electron oxidation of indole-3-acetic acid (IAA) and its ring-substituted derivatives rapidly fragment, eliminating carbon dioxide from the sidechain and forming a carbon-centred free radical (3-indolylmethyl or skatolyl, or analogues). This radical is reactive towards DNA and possibly other targets in anoxia, but in oxic or hypoxic cells rapidly adds oxygen to form a peroxyl radical. Subsequent products include 3-methylene-2-oxindole or analogues, reactive towards cellular nucleophiles such as thiols and DNA. The one-electron oxidation of indole-3-acetic acids is efficiently achieved by horseradish peroxidase (HRP), not requiring added hydrogen peroxide cofactor. The combination of IAA and HRP is cytotoxic towards mammalian cells, including human tumour cells. Unexpectedly, some halogen-substituted derivatives of IAA are very cytotoxic with HRP even though they are more difficult to oxidize. IAA is tolerated by humans in high doses and HRP is a robust enzyme meeting many of the requirements for targeting to tumours by coupling to antibodies or polymers, or by gene transfection. It is suggested that the indole acetic acids merit further evaluation as potential prodrugs for use in cancer therapy based on targeted delivery of HRP to tumours.