While
reactive oxygen species (ROS) gain their carcinogenic effects by
DNA mutations, if generated in the vicinity of genome, lipid peroxidation products, notably
4-hydroxynonenal (HNE), have much more complex modes of activities. Namely, while ROS are short living and have short efficiency distance range (in nm or µm) HNE has strong binding affinity for
proteins, thus forming relatively stable adducts. Hence, HNE can diffuse from the site or origin changing structure and function of respective
proteins. Consequently HNE can influence proliferation, differentiation and apoptosis of
cancer cells on one hand, while on the other it can affect genome functionality, too. Although HNE is considered to be important factor of
carcinogenesis due to its ability to covalently bind to
DNA, it might also be cytotoxic for
cancer cells, as well as it can modulate their growth. In addition to direct cytotoxicity, HNE is also involved in activity mechanisms by which several
cytostatic drugs and
radiotherapy exhibit their anticancer effects. Complementary to that, the metabolic pathway for HNE detoxification through RLIP76, which is enhanced in
cancer, may be a target for anti-
cancer treatments. In addition, some
cancer cells can undergo apoptosis or
necrosis, if exposed to supraphysiological HNE levels in the cancer microenvironment, especially if challenged additionally by pro-oxidative
cytostatics and/or
inflammation. These findings could explain previously observed disappearance of HNE from invading
cancer cells, which is associated with the increase of HNE in non-malignant cells close to invading
cancer utilizing
cardiolipin as the source of
cancer-inhibiting HNE.