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MTH1 as a Chemotherapeutic Target: The Elephant in the Room.

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.

SUBMITTER: Samaranayake GJ

PROVIDER: S-EPMC5447957 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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MTH1 as a Chemotherapeutic Target: The Elephant in the Room.

Samaranayake Govindi J GJ Huynh Mai M Rai Priyamvada P

Cancers 20170508 5

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 mechan ...[more]

PMID: 28481306

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Project description:Radiocarbon (14C) analysis of skeletal remains by accelerator mass spectrometry is an essential tool in multiple branches of science. However, bone 14C dating results can be inconsistent and not comparable due to disparate laboratory pretreatment protocols that remove contamination. And, pretreatments are rarely discussed or reported by end-users, making it an 'elephant in the room' for Quaternary scientists. Through a questionnaire survey, I quantified consensus on the reliability of collagen pretreatments for 14C dating across 132 experts (25 countries). I discovered that while more than 95% of the audience was wary of contamination and would avoid gelatinization alone (minimum pretreatment used by most 14C facilities), 52% asked laboratories to choose the pretreatment method for them, and 58% could not rank the reliability of at least one pretreatment. Ultrafiltration was highly popular, and purification by XAD resins seemed restricted to American researchers. Isolating and dating the amino acid hydroxyproline was perceived as the most reliable pretreatment, but is expensive, time-consuming and not widely available. Solid evidence supports that only molecular-level dating accommodates all known bone contaminants and guarantees complete removal of humic and fulvic acids and conservation substances, with three key areas of progress: (i) innovation and more funded research is required to develop affordable analytical chemistry that can handle low-mass samples of collagen amino acids, (ii) a certification agency overseeing dating-quality control is needed to enhance methodological reproducibility and dating accuracy among laboratories, and (iii) more cross-disciplinary work with better 14C reporting etiquette will promote the integration of 14C dating across disciplines. Those developments could conclude long-standing debates based on low-accuracy data used to build chronologies for animal domestications, human/megafauna extirpations and migrations, archaeology, palaeoecology, palaeontology and palaeoclimate models.

Dataset Information

MTH1 as a Chemotherapeutic Target: The Elephant in the Room.

Publications

MTH1 as a Chemotherapeutic Target: The Elephant in the Room.

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