The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress.

Sep 17, 2002Clinical cancer research : an official journal of the American Association for Cancer Research

A DNA repair enzyme helps human brain tumor cells resist chemotherapy and increases with oxidative stress

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Abstract

Ape1/Ref-1 contributes to alkylating agent resistance in human glioma cells by incising DNA at abasic sites.

Reduction of Ape1/Ref-1 protein and activity in SNB19 glioma cells leads to decreased resistance against alkylating agents.
Antisense oligonucleotides targeting Ape1/Ref-1 result in higher levels of abasic sites in DNA.
Exposure to reactive oxygen species (ROS) increases Ape1/Ref-1 levels and activity, enhancing resistance to alkylating agents.
Elevated oxidative stress in brain tumors may influence their response to alkylating agent-based chemotherapy.
Findings could inform the design of treatment regimens combining ionizing radiation and alkylating agents.

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Alkylating agents are standard components of adjuvant chemotherapy for gliomas. We provide evidence here that Ape1/Ref-1, the major mammalian apurinic/apyrimidinic endonuclease (Ap endo), contributes to alkylating agent resistance in human glioma cells by incising DNA at abasic sites. We show that antisense oligonucleotides directed against Ape1/Ref-1 in SNB19, a human glioma cell line lacking O(6)-methylguanine-DNA-methyltransferase, mediate both reduction in Ape1/Ref-1 protein and Ap endo activity and concurrent reduction in resistance to methyl methanesulfonate and the clinical alkylators temozolomide and 1,3-(2-chloroethyl)-1-nitrosourea. An accompanying increase in the level of abasic sites indicates that the DNA repair activity of Ape1/Ref-1 contributes to resistance. Conversely, we also show that exposure of SNB19 cells to HOCl, a generator of reactive oxygen species (ROS), results in elevated Ape1/Ref-1 protein and Ap endo activity, enhanced alkylator resistance, and reduced levels of abasic sites. Given current evidence that heightened oxidative stress prevails within brain tumors, the finding that ROS increase resistance to clinical alkylators in glioma cells may have significance for the response of gliomas to alkylating agent-based chemotherapy. Our results may also be relevant to the design of therapeutic regimens using concurrent ionizing radiation (a generator of ROS) and alkylating agent-based chemotherapy.

The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress.

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