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MTH1 as a Chemotherapeutic Target: The Elephant in the Room

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 ele...

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Autores principales: Samaranayake, Govindi J., Huynh, Mai, Rai, Priyamvada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447957/
https://www.ncbi.nlm.nih.gov/pubmed/28481306
http://dx.doi.org/10.3390/cancers9050047
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author Samaranayake, Govindi J.
Huynh, Mai
Rai, Priyamvada
author_facet Samaranayake, Govindi J.
Huynh, Mai
Rai, Priyamvada
author_sort Samaranayake, Govindi J.
collection PubMed
description 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.
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spelling pubmed-54479572017-05-30 MTH1 as a Chemotherapeutic Target: The Elephant in the Room Samaranayake, Govindi J. Huynh, Mai Rai, Priyamvada Cancers (Basel) Review 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. MDPI 2017-05-08 /pmc/articles/PMC5447957/ /pubmed/28481306 http://dx.doi.org/10.3390/cancers9050047 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Samaranayake, Govindi J.
Huynh, Mai
Rai, Priyamvada
MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title_full MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title_fullStr MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title_full_unstemmed MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title_short MTH1 as a Chemotherapeutic Target: The Elephant in the Room
title_sort mth1 as a chemotherapeutic target: the elephant in the room
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447957/
https://www.ncbi.nlm.nih.gov/pubmed/28481306
http://dx.doi.org/10.3390/cancers9050047
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