MTH1 Inhibitors for the Treatment of Psoriasis

Florence Sjögren,Ulrika Warpman Berglund,Therese Pham,Charlotta Enerbäck,Martin Scobie,Stella Karsten,Thomas Helleday,Deepti Verma,Claudia Bamberg,Cecilia Bivik Eding,Ines Köhler

doi:10.1016/j.jid.2021.01.026

Abstract

Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17‒associated cytokines in the skin, which was in line with decreased levels of IL-17-producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17‒downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application as a promising therapeutic approach to psoriasis.

Highlights

ROS are produced during normal cellular metabolism and may damage biological macromolecules such as lipids, proteins, and DNA (Valko et al, 2007)
The sensitivity to MTH1 inhibition in keratinocytes correlates with ROS levels The cell death‒inducing potential of five different MTH1 inhibitor (MTH1i) was evaluated in normal human epidermal keratinocytes, neonatal (HEKn) cells (Cascade Biologics, Portland, OR); in precancerous dysplastic oral keratinocyte (DOK) cell line
L-buthionine sulfoximine treatment resulted in an accumulation of 8-oxo-dGTP, which was further augmented by MTH1 inhibition (Figure 2g). These results show that the apoptosis-inducing potential of the MTH1is in KCs is associated with the severity of the oxidative stress

Summary

Introduction

ROS are produced during normal cellular metabolism and may damage biological macromolecules such as lipids, proteins, and DNA (Valko et al, 2007). To counteract the damaging effects of increased ROS production, cells upregulate antioxidant defense mechanisms, including the human MTH1. MTH1 prevents oxidized nucleotide triphosphates, such as 8-oxodeoxyguanosine triphosphate (8-oxo-dGTP) and 2-hydroxy-2-deoxyadenosine triphosphate (2-OH-dATP), from being incorporated into genomic DNA (Sakumi et al, 1993). This in turn prevents genomic instability, DNA damage, and cell death. MTH1 expression is induced in cancer cell lines and in a wide range of solid tumors, including breast (Zhang et al, 2017), lung (Fujishita et al, 2017), and colorectal (Koketsu et al, 2004) cancers as a result of increased oxidative. MTH1 activity is dispensable (Tsuzuki et al, 2001)

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Conclusion