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Cancers 2017, 9(5), 47; doi:10.3390/cancers9050047

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

1
Department of Medicine/Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
2
Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami, Miami, FL 33136, USA
3
College of Arts and Sciences, University of Miami, Coral Gables, FL 33146, USA
4
Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Eddy S. Yang
Received: 25 March 2017 / Revised: 29 April 2017 / Accepted: 29 April 2017 / Published: 8 May 2017
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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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. View Full-Text
Keywords: MTH1; oxidative stress; cancer; therapeutic target; nucleotide pool; p53; RAS oncogene; MTH1 inhibitors MTH1; oxidative stress; cancer; therapeutic target; nucleotide pool; p53; RAS oncogene; MTH1 inhibitors
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Samaranayake, G.J.; Huynh, M.; Rai, P. MTH1 as a Chemotherapeutic Target: The Elephant in the Room. Cancers 2017, 9, 47.

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