Abstract
Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target.
Highlights
Human MutT Homolog 1 (MTH1 a.k.a Nudix hydrolase 1, NUDT1) is an 18 kD Nudix pyrophosphatase that hydrolyzes the oxidized purine deoxyribonucleotides, 8-oxo-dGTP, as well as the less frequently-occurring 2-OH-dATP and 8-oxo-dATP, and their ribonucleotide analogs into their monophosphate equivalents [1,2,3,4]
Recent studies with the first wave of MutT Homolog1 (MTH1) inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target
To address the proverbial “elephant in the room” as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target
Summary
Human MutT Homolog 1 (MTH1 a.k.a Nudix hydrolase 1, NUDT1) is an 18 kD Nudix pyrophosphatase that hydrolyzes the oxidized purine deoxyribonucleotides, 8-oxo-dGTP, as well as the less frequently-occurring 2-OH-dATP and 8-oxo-dATP, and their ribonucleotide analogs into their monophosphate equivalents [1,2,3,4] These enzymatic byproducts are targeted for degradation to prevent their re-use by deoxyribonucleotide salvage pathways [3]. MTH1 has been reported to hydrolyze 2-OH-dATP more efficiently than 8-oxo-dGTP [14], the high intracellular abundance of 8-oxo-dGTP [5] makes the functional 8-oxo-dGTPase activity of MTH1 more physiologically relevant to biological systems.
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