Background
Cancer cells often have dysfunctional redox regulation that produces high levels of intracellular reactive oxygen species, which oxidizes dNTPs leading to damage to DNA. MTH1hydrolyzes oxidized dNTPs thus protecting cells from DNA damage. Inhibition of MTH1 by specific inhibitors is emerging as a promising approach in the treatment of various types of cancer. However, the effect of MTH1 inhibitors in human melanoma remains less understood.
Aims
To define the effect of inhibition of MTH1 on melanoma cell survival, and to determine the therapeutic potential of MTH1 inhibitors in the treatment of melanoma.
Results
While MTH1was commonly upregulated in melanoma cells in vitro and in vivo, treatment with the MTH1 inhibitor TH588 potently induced cell death in the majority of melanoma cell lines tested. Killing of melanoma cells by TH588 was associated with activation of the mitochondrial apoptotic pathway and the caspase cascade, and was inhibitable by the general caspase inhibitor z-VAD-fmk, indicative of induction of apoptosis. Moreover, differential regulation of pro-apoptotic Bcl-2 family proteins appeared to play an important role in determining sensitivity of melanoma cells to TH588-induced apoptosis. Induction of apoptosis by TH588 was consolidated in fresh melanoma isolates and melanoma cells grown in 3-dimentional cultures.
Conclusions
The above results indicate that MTH1 expression is upregulated in melanoma cells, and that the MTH1 inhibitor TH588 is a promising therapeutic agent in the treatment of melanoma.
Translational research aspect
This project is currently at T1 stage. However, it is expected to be taken into pre-clinical studies in near future, which will be followed by evaluation in clinical trials.