In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity.

Nobuyoshi Fukumitsu,William Tong,Uday Mukhopadhyay,Skye Hsin-Hsien Yeh,Hwan-Jeong Jeong,Juri G Gelovani,Leo Garcia Flores Ii,Kazuma Ogawa,Daniel Young

doi:10.1155/2018/3612027

Abstract

Background Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

Highlights

Acetylation and deacetylation on different positions of the Nterminal tail of core histones by histone acetylases (HATs) and histone deacetylases (HDACs) change the nucleosomal conformation of cells [1]
We demonstrated that the rapid [18F]FAHA accumulation in the brains of rats and rhesus macaques and the rate of [18F]FAHA accumulation were dose-dependently inhibited by the pan-Histone deacetylases (HDACs) inhibitor, Suberoylanilide hydroxamic acid (SAHA)
The Ki value of [18F]FAHA of the brain was significantly increased after cisplatin administration in Groups A and B (Figures 1(a), 1(b), and 2)

Summary

Introduction

Acetylation and deacetylation on different positions of the Nterminal tail of core histones by histone acetylases (HATs) and histone deacetylases (HDACs) change the nucleosomal conformation of cells [1]. The protein concentration and enzymatic activities of HATs and HDACs are carefully balanced. Such equilibrium regulates cellular homeostasis and gene expression to facilitate normal cell function and activity. Disrupted equilibrium with stronger activity in the deacetylase system leads to transcriptional repression of a diverse set of genes [2, 3]. Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment

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Conclusion