Short-Chain Fatty Acid Inhibitors of Histone Deacetylases: Promising Anticancer Therapeutics?

Abstract

Cancer is a disease in which cellular growth regulatory networks are disrupted. Lesions in well-characterized oncogenes and tumor suppressors often contribute to the dysregulation, but recent work has also uncovered the fundamental importance of enzymes that modulate the acetylation status of chromatin to the initiation or progression of cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to be involved in physiological cellular processes, such as transcription, cell cycle progression, gene silencing, differentiation, DNA replication, and genotoxic responses, but they are also increasingly being implicated in tumorigenesis. Butyrate is a short-chain fatty acid (SCFA) that acts as a HDAC inhibitor and is being clinically evaluated as an anti-neoplastic therapeutic, primarily because of its ability to impose cell cycle arrest, differentiation, and/or apoptosis in many tumor cell types, and its favorable safety profile in humans. Additionally, HDAC inhibitors could be used in combination with certain established antitumor therapeutics, such as those that target transcription, to augment clinical efficacy, and/or reduce toxicity. The molecular pathways of butyrate and related next-generation synthetic SCFAs in mediating these effects have not been fully elucidated, but HDAC inhibition is associated with regulation of critical cell cycle regulators, such as cyclin D, p21(CIP1/WAF1), and p27(KIP1). It is anticipated that a better understanding of this critical intersection between SCFAs, HDACs, and cell cycle control will lead to the design of novel treatment strategies for neoplasias. This review will summarize some of the recent research in these arenas of HDAC-directed cancer therapy and discuss the potential application of these agents in synergy with current chemotherapeutics.

Interaction between Protein Kinase Cμ and the Vanilloid Receptor Type 1

“…Histone deacetylase inhibitors are attracting interest as potential therapeutics (23). Our findings imply that their possible effects on C-fiber function through modulation of PKC expression should be carefully evaluated.…”

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

“…It cannot be ruled out that the observed changes could be a parallel issue as for example growth inhibition, induced by sodium butyrate, has been described in a cell line that has abrogated Rb function (Rashid et al, 2001). There might be other and potentially even more important structures such as cyclin A and D, p27 and protein kinase C, which are involved in the process of butyrate-induced growth inhibition (Chen et al, 2003;Kim et al, 2003;Siddiqui et al, 2003). Nevertheless, exploring the activation of p-21, including the role of Sp1 transcription factor, is a very promising approach (Wang et al, 2000;Rashid et al, 2001;Margueron et al, 2003), as this gene appears to be rarely mutated in common human malignancies in contrast to p53 (Terao et al, 2001).…”

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

“…The short-chain fatty acid sodium butyrate is capable of inducing cell cycle arrest, differentiation, and apoptosis in a variety of cancer cells (Chen et al, 2003). In human glioma cells, sodium butyrate has been shown to inhibit proliferation through modulation of the protein levels of various cell cycle regulators Kamitani et al, 2002).…”