Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy

Biofactors. 2022 Mar;48(2):384-399. doi: 10.1002/biof.1789. Epub 2021 Oct 4.


A number of approaches have been developed over the years to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. Here, enzymes can also find useful applications. Among them, oxidases have attracted attention because of their ability to produce reactive oxygen species (ROS, especially hydrogen peroxide) in tumors and potentially modulate the production of this cytotoxic compound when enzymes active on substrates present in low amounts are used, such as the d-amino acid oxidase and d-amino acid couple system. These treatments have been also developed for additional cancer treatment approaches, such as phototherapy, nutrient starvation, and metal-induced hydroxyl radical production. In addition, to improve tumor specificity and decrease undesired side effects, oxidases have been targeted by means of nanotechnologies and protein engineering (i.e., by designing chimeric proteins able to accumulate in the tumor). The most recent advances obtained by using six different oxidases (i.e., the FAD-containing enzymes glucose oxidase, d- and l-amino acid oxidases, cholesterol oxidase and xanthine oxidase, and the copper-containing amine oxidase) have been reported. Anticancer therapy based on oxidase-based ROS production has now reached maturity and can be applied in the clinic.

Keywords: cancer therapy; cytotoxicity; drug delivery; enzyme prodrug therapy; flavoprotein oxidases; nanoparticles; nanoreactors; oxidative stress; reactive oxygen species.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism


  • Antineoplastic Agents
  • Reactive Oxygen Species