RT Journal Article
SR Electronic
T1 Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 970
OP 981
DO 10.1124/mol.115.099614
VO 88
IS 6
A1 Ufuk Ozer
A1 Karen W. Barbour
A1 Sarah A. Clinton
A1 Franklin G. Berger
YR 2015
UL http://molpharm.aspetjournals.org/content/88/6/970.abstract
AB Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2ʹ-deoxyuridine-5ʹ-monophosphate (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 defense 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.