Monitoring Histone Deacetylase Inhibition In Vivo: Noninvasive Magnetic Resonance Spectroscopy Method

Abstract

Histone deacetylase inhibitors (HDACis) are emerging as promising and selective antitumor agents. However, HDACis can lead to tumor stasis rather than shrinkage, in which case, traditional imaging methods are not adequate to monitor response. Consequently, novel approaches are needed. We have shown in cells that (19)F magnetic resonance spectroscopy (MRS)-detectable levels of the HDAC substrate Boc-Lys-TFA-OH (BLT) are inversely correlated with HDAC activity. We extended our investigations to a tumor xenograft model. Following intraperitoneal injection of BLT, its accumulation within the tumor was monitored by in vivo (19)F MRS. In animals treated with the HDACi suberoylanilide hydroxamic acid (SAHA), tumoral BLT levels were higher by 77% and 132% on days 2 and 7 of treatment compared with pretreatment levels (n = 6; p < .05). In contrast, tumoral BLT levels remained unchanged in control animals and in normal tissue. Thus, (19)F MRS of BLT detected the effect of HDACi treatment as early as day 2 of treatment. Importantly, tumor size confirmed that SAHA treatment leads to inhibition of tumor growth. However, difference in tumor size reached significance only on day 6 of treatment. Thus, this work identifies BLT as a potential molecular imaging agent for the early noninvasive MRS detection of HDAC inhibition in vivo.

Metabolic Tumor Imaging Using Magnetic Resonance Spectroscopy

“…However, PC levels did not change following HDAC inhibition in tumors in vivo. 110 A novel fluorinated lysine derivative, which is a cleavable substrate for HDAC that can detect HDAC activity monitored by 19 F MRS, was also described in the same study. 110 …”

“…While a decrease of tCho and PC was observed following treatments against molecular targets such as mitogen-activated protein kinase (MAPK), 107 fatty acid synthase, 108 and Bcr-Abl tyrosine kinase, 109 PC levels were found to increase following histone deacetylase (HDAC) inhibition. 110 Therefore, a decrease of tCho or PC cannot always be associated with response, as this will depend on the target selected. However, PC levels did not change following HDAC inhibition in tumors in vivo.…”

Magnetic Resonance Spectroscopy in Metabolic and Molecular Imaging and Diagnosis of Cancer

“…mitogen activatived protein kinase (MAPK),186 fatty acid synthase,187 and Bcr-Abl tyrosine kinase,188 the decrease of tCho or PC cannot always be associated with response, and depends upon the target selected. This was exemplified in a study showing that PC levels increased following histone deacetylase (HDAC) inhibition in cells 189. However, PC levels did not change in tumors in vivo following HDAC inhibition 189.…”

“…This was exemplified in a study showing that PC levels increased following histone deacetylase (HDAC) inhibition in cells 189. However, PC levels did not change in tumors in vivo following HDAC inhibition 189. This study also describes a novel fluorinated lysine derivative, which is a cleavable HDAC substrate that can be monitored by 19 F MRS to detect HDAC activity 189…”

Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

“…HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, appears to be an important determinant of HDI sensitivity and may be highly expressed in CTCL [220]. Non-invasive magnetic resonance spectroscopy using artificial HDAC substrates may also be applicable for analysis of HDAC inhibition in vivo [221].…”