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.
| Original language | English (US) |
|---|---|
| Article number | 47 |
| Journal | Cancers |
| Volume | 9 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 8 2017 |
Fingerprint
Keywords
- Cancer
- MTH1
- MTH1 inhibitors
- Nucleotide pool
- Oxidative stress
- P53
- RAS oncogene
- Therapeutic target
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
MTH1 as a chemotherapeutic target : The elephant in the room. / Samaranayake, Govindi J.; Huynh, Mai; Rai, Priyamvada.
In: Cancers, Vol. 9, No. 5, 47, 08.05.2017.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - MTH1 as a chemotherapeutic target
T2 - The elephant in the room
AU - Samaranayake, Govindi J.
AU - Huynh, Mai
AU - Rai, Priyamvada
PY - 2017/5/8
Y1 - 2017/5/8
N2 - 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.
AB - 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.
KW - Cancer
KW - MTH1
KW - MTH1 inhibitors
KW - Nucleotide pool
KW - Oxidative stress
KW - P53
KW - RAS oncogene
KW - Therapeutic target
UR - http://www.scopus.com/inward/record.url?scp=85019141573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019141573&partnerID=8YFLogxK
U2 - 10.3390/cancers9050047
DO - 10.3390/cancers9050047
M3 - Review article
AN - SCOPUS:85019141573
VL - 9
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 5
M1 - 47
ER -