Rational Combinations Using HDAC Inhibitors

Abstract

In addition to well-characterized genetic abnormalities that lead to cancer onset and progression, it is now recognized that alterations to the epigenome may also play a significant role in oncogenesis. As a result, epigenetic-modulating agents such as histone deacetylase inhibitors (HDACi) have attracted enormous attention as anticancer drugs. In numerous in vitro and preclinical settings, these compounds have shown their vast potential as single agent anticancer therapies, but unfortunately equivalent responses have not always been observed in patients. Given the pleiotropic effects HDACi have on malignant cells, their true therapeutic potential most likely lies in combination with other anticancer drugs. In this review we will focus on the anticancer effects of HDACi when combined with other cancer therapeutics with an emphasis on those combinations based on a strong molecular rationale.

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Accumulating evidence sustains that impairing the acetylation/deacetylation balance in favor of acetylation, by the use of HDACi, may be therapeutically exploited in patients with hematological and solid malignancies (Bolden et al, 2006;Piekarz et al, 2007;Bots, 2009;Mercurio et al, 2010). However, the mechanisms underlying HDACi action are not entirely understood as yet.…”

Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells

“…5,10 Thus, HDAC inhibitors (HDACi), due to their ability to reactivate epigenetically silenced genes that are essential for abrogating cancer cell survival and proliferation, are gaining interest as potential anticancer drugs. 5,12,13 HDACi are categorized into short chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides 5 and have shown therapeutic potential in pre-clinical studies, but have mostly failed as monotherapies against solid tumors in clinical settings 5,13,14 [with the exception of hematological malignancies, expression. 5,10 To assess whether silibinin-mediated HDAC inhibition increased histone acetylation, levels of acetylated histone H3 (Ac-H3) and Ac-H4 were analyzed from similar silibinintreated H1299 cells.…”

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

“…For instance, histone deacetylase (HDAC) inhibitors were primarily developed to oppose transcriptional repression mediated by altered oncogenic transcription factors, which repress transcription through HDAC in many patients with acute myeloid leukemia. These have ultimately shown efficacy only in cutaneous T-cell lymphomas through poorly understood mechanisms (14). Similarly, targeting the activation of FLT3 kinase, a common progression event in many different subtypes of leukemia, failed to yield clinical benefit (15).…”