PT  - JOURNAL ARTICLE
AU  - Ufuk Ozer
AU  - Karen W. Barbour
AU  - Sarah A. Clinton
AU  - Franklin G. Berger
TI  - Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites
AID  - 10.1124/mol.115.099614
DP  - 2015 Jan 01
TA  - Molecular Pharmacology
PG  - mol.115.099614
4099  - http://molpharm.aspetjournals.org/content/early/2015/10/06/mol.115.099614.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/10/06/mol.115.099614.full
AB  - Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of dUMP by N5,N10-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors, and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O2 to generate superoxide (O2·-), is a significant source of increased ROS levels in drug-treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of protection against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.