Abstract
Simple SummaryLiver cancers are among the leading causes of global cancer deaths. The current therapy options for liver cancers, including hepatocellular carcinoma (HCC), which accounts for over 80% of all cases, have afforded limited benefit to patients with an advanced disease state. HCC results from genetic and epigenetic alterations, including gene-silencing chromatin histone hypoacetylation. The aim of this study was to investigate the potential utility of liver tissue-targeting HDAC inhibitors (HDACi) as a new class of anti-HCC agents. We showed that a class of macrolide-based HDACi, which are selective for sub-class I HDACs, preferentially accumulated in the liver tissue and robustly suppressed tumor growths in an orthotopic model of HCC. The liver tissue-selective accumulation property of these compounds gives them a unique advantage over most of the current HDACi, including those currently in clinical use.Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. Inhibition of the deacetylase activity of HDACs is a clinically validated cancer therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent histone H4 hyperacetylation without perturbation of tubulin acetylation status and G0/G1 cell cycle arrest. Representative compounds 2 and 3a are relatively non-toxic to mice and robustly suppressed tumor growths in an orthotopic model of HCC as standalone agents. Collectively, our results suggest that these compounds may have therapeutic advantage against HCC relative to the current systemic HDACi. This prospect merits further comprehensive preclinical investigations.
Highlights
Liver cancer is among the leading causes of global cancer deaths, with an incidence and mortality two to three times higher among men in most regions of the world [1]
We disclosed a class of HDAC inhibitors (HDACi) that are selective for sub-class I Histone deacetylases (HDACs), preferentially for sub-class I HDACs, preferentially accumulate in the liver tissue and are relatively non-toxic to accumulate in the liver tissue and are relatively non-toxic to mice
We showed in prior studies that appending macrolides as secondary moieties to the surface recognition cap group of prototypical HDACi resulted in a novel class of non-peptide macrocyclic
Summary
Liver cancer is among the leading causes of global cancer deaths, with an incidence and mortality two to three times higher among men in most regions of the world [1]. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for over 80% of all cases, and occurring in >90% of cases in patients with liver damage. Liver transplant has proven successful in treating cases of early stage HCC, but only an even smaller proportion of patients are eligible due to the late diagnosis of the disease and limited organ availability [5,6]. Other local strategies, such as transarterial chemo-embolization, radioembolization, and radiofrequency ablation, are largely palliative [7]
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