Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1

Wang, Mian; Zhou, Shuilian; Chen, Qing; Wang, Lisheng; Liang, Zhiqun; Wang, Jianyi

doi:10.1038/srep40557

Cited by 9 publications

(6 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By contrast, ( S )-crizotinib potently inhibited c-MET and ErbB3 phosphorylation, similar to its ( R )-enantiomer. Thus, while the MTH1-binding capacity of both drugs is not in question 8,9,15,16,19,30 , the effects on CRC cell survival do not seem to be due to inhibition of MTH1, as they are unaffected by experimental manipulation of ROS levels. Our results obtained in 3D model systems are in line with previous work in other model systems and other cancer types showing MTH1-independent anti-tumour effects of TH588 and ( S )-crizotinib 15–19 .…”

Section: Discussionmentioning

confidence: 93%

Differential anti-tumour effects of MTH1 inhibitors in patient-derived 3D colorectal cancer cultures

Waals

Laoukili

Raats

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Reactive oxygen species (ROS) function as second messengers in signal transduction, but high ROS levels can also cause cell death. MTH1 dephosphorylates oxidized nucleotides, thereby preventing their incorporation into DNA and protecting tumour cells from oxidative DNA damage. Inhibitors of MTH1 (TH588 and (S)-crizotinib) were shown to reduce cancer cell viability. However, the MTH1-dependency of the anti-cancer effects of these drugs has recently been questioned. Here, we have assessed anti-tumour effects of TH588 and (S)-crizotinib in patient-derived 3D colorectal cancer cultures. Hypoxia and reoxygenation – conditions that increase intracellular ROS levels – increased sensitivity to (S)-crizotinib, but not to TH588. (S)-crizotinib reduced tyrosine phosphorylation of c-MET and ErbB3 whereas TH588 induced a mitotic cell cycle arrest, which was not affected by adding ROS-modulating compounds. Furthermore, we show that both compounds induced DNA damage that could not be prevented by adding the ROS inhibitor N-acetyl-L-cysteine. Moreover, adding ROS-modulating compounds did not alter the reduction in viability in response to TH588 and (S)-crizotinib. We conclude that TH588 and (S)-crizotinib have very clear and distinct anti-tumour effects in 3D colorectal cancer cultures, but that these effects most likely occur through distinct and ROS-independent mechanisms.

show abstract

Section: Discussionmentioning

confidence: 93%

Differential anti-tumour effects of MTH1 inhibitors in patient-derived 3D colorectal cancer cultures

Waals

Laoukili

Raats

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…While some recent articles reported that MTH1 may not be an independent anti-cancer target, [ 33 – 35 ] there is no doubt that MTH1 is a target of cellular antioxidative defenses [ 1 , 36 – 38 ]. For both normal and cancerous cells, it is not uncommon that different cells have different sensitivities to MTH1 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Thus cancer cells with shorten telomere would be more sensitive to MTH1 inhibition and the oxidative stress [ 1 ]. The inhibition or disruption of MTH1 is sure to reduce the cell's ability to cope with oxidative stress, especially for cancer cells [ 1 – 4 , 36 ]. MTH1, which protects cancer cells from the oxidative-stress-induced damage of dNTP pools, is a promising target for designing effective anti-cancer drugs with low toxicities [ 1 – 4 , 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

et al. 2017

View full text Add to dashboard Cite

Cancer cells are more addictive to MTH1 than normal cells because of their dysfunctional redox regulations. MTH1 plays an important role to maintain tumor cell survival, while it is not indispensable for the growth of normal cells. Farnesyl phenols having a coumaroyl substitution are rather uncommon in nature. Eight farnesyl phenolic compounds with such substituent moiety (1–8), including six new ones, ganosinensols E–J (1–6) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense. Four pairs of enantiomers 1/2, 3/4, 5/6 and 7/8 were resolved by HPLC using a Daicel Chiralpak IE column. Their structures were elucidated from extensive spectroscopic analyses and comparison with literature data. The absolute configurations of C-1′ in 1–6 were assigned by ECD spectra. These compounds were predicted to have high binding affinity to MTH1 through virtual ligand screening. The enzyme inhibition experiments and cell-based assays confirmed their inhibitory effects on MTH1. Furthermore, siRNA knockdown experiments and the cellular thermal shift assay (CETSA) confirmed that the farnesyl phenolic enantiomers specifically bound with MTH1 in intact cells. Meanwhile, the low cytotoxicity of 1–8 on normal human cells further verified their good selectivity and specificity to MTH1. These active structures are expected to be potential anti-cancer lead compounds.

show abstract

“…Consequently, targeting this enzymatic function has been proposed to induce single strand breaks and G:C to T:A transversion mutations during DNA replication [ 5 ]. The MTH1 inhibitor TH588 was identified by Gad and co-authors in 2014 [ 6 ] and has been used in several studies subsequently [ 7 – 9 ]. Other investigators have generated inhibitors independently as reviewed very recently [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

et al. 2018

View full text Add to dashboard Cite

BackgroundThe nudix family member enzyme MutT homologue-1 (MTH1) hydrolyses the oxidized nucleotides 8-oxo-dGTP and 2-hydroxy-dATP and thus prevents the incorporation of damaged nucleotides into nuclear and mitochondrial DNA. Therefore MTH1 was proposed to protect cancer cells from oxidative DNA lesions and subsequent cell death. We investigated whether the bona fide MTH1 inhibitor TH588 affects responses of cultured colorectal tumor cells to ionizing radiation (IR) in normoxia and in moderate or severe hypoxia.MethodsTH588 was tested in cell viability and survival assays (tetrazolium dye (MTT), propidium iodide staining, caspase-3 activity, and colony formation assays (CFA)) in colorectal carcinoma cells (HCT116 and SW480) in combination with IR in normoxia and in hypoxia. Additionally, MTH1 was targeted by lentiviral shRNA expression. Human umbilical vein endothelial cells (HUVEC) were assessed in MTT assays.ResultsIn all cell lines tested, TH588 dose-dependently impaired cell survival. In CFAs, TH588 and IR effects on carcinoma cells were additive in normoxia and in hypoxia. Using 3 different shRNAs, the lentiviral approach was detrimental to SW480, but not to HCT116.ConclusionsTH588 has cytotoxic effects on transformed and untransformed cells and synergizes with IR in normoxia and in hypoxia. TH588 toxicity is not fully explained by MTH1 inhibition as HCT116 were unaffected by lentiviral suppression of MTH1 expression. TH588 should be explored further because it has radiosensitizing effects in hypoxia.

show abstract

Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1

Cited by 9 publications

References 42 publications

Differential anti-tumour effects of MTH1 inhibitors in patient-derived 3D colorectal cancer cultures

Differential anti-tumour effects of MTH1 inhibitors in patient-derived 3D colorectal cancer cultures

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

Contact Info

Product

Resources

About