Cancer and Metastasis Reviews

, Volume 30, Issue 3–4, pp 437–447 | Cite as

Cyclooxygenase- and lipoxygenase-mediated DNA damage

  • N. Speed
  • I. A. BlairEmail author


Cancer is a disease of aging, and so with the increasing age of the US population, the incidence of cancer is also increasing. Furthermore the global burden of cancer continues to increase largely because of aging and growth of the world population together with increasing smoking rates in economically developing countries. Tumor formation is critically dependent upon two processes—initiation and progression. The initiation step is mediated by DNA damage, which causes activating mutations in proto-oncogenes and inactivation of tumor suppressor genes in many cancers. This is then thought to facilitate tumor progression and metastasis. Cyclooxygenase-2 (COX-2) is upregulated at an early stage in tumorigenesis and has been implicated as an important mediator of proliferation through the increased formation of bioactive arachidonic acid (AA) metabolites such as prostaglandin E2. Significantly, we have found that COX-2-mediated AA metabolism also results in the formation of heptanone-etheno (Hε)-DNA adducts. Furthermore, we showed that the Hε-DNA adducts arose from the reaction of DNA with the lipid hydroperoxide-derived bifunctional electrophile, 4-oxo-2(E)-nonenal (ONE). Similarly, 5-lipoxoygenase-mediated AA metabolism also results in the formation of ONE-derived DNA adducts. The resulting Hε-DNA adducts are highly mutagenic in mammalian cell lines suggesting that these pathways could be (in part) responsible for the somatic mutations observed in tumorigenesis. As approximately 80% of cancers arise from somatic mutations, this provides an additional link between the upregulation of COX-2 and tumorigenesis.


Lipid peroxidation DNA adducts Somatic mutations Tumorigenesis 



This work was supported by NIH grants R01CA091016, P30ES013508, and R25CA101871.


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Centers for Cancer Pharmacology and Excellence in Environmental ToxicologyUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

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