Selective inhibition of HDAC6 sensitizes cutaneous T‑cell lymphoma to PI3K inhibitors

Abstract

Histone deacetylase (HDAC) inhibitors, approved for the treatment of cutaneous T-cell lymphoma (CTCL), are non-selective agents associated with an unsatisfactory response and considerable side-effects. Targeting single HDAC isoforms is considered to provide novel therapeutic options. HDAC6 is overexpressed in primary samples from patients with CTCL and preclinical studies using transgenic mice that spontaneously develop a CTCL-like disease, have suggested that combinations including HDAC6 inhibitors may be successful in the treatment of CTCL. PI3K inhibition is currently being tested in clinical trials for CTCL with promising results. Since HDAC6 is known to diminish the activity of Akt via its deacetylation, the aim of the present study was to evaluate the therapeutic potential of selective HDAC6 inhibitors in combination with PI3K inhibitors in CTCL. Through the genetic and pharmacological inhibition of HDAC6, it was demonstrated that combining HDAC6 with PI3K inhibition may be an attractive therapeutic option for patients with CTCL.

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

“…IL-15 is a significant component in the pathogenesis of CTCLs, as the overexpression of IL-15 induces spontaneous CTCL and MF progression ( 9 – 11 ). The inhibition of HDAC6 and the presence of PI3K inhibitors were observed to synergistically inhibit cell proliferation in CTCL cell lines ( 12 ) ( Figure 1 ). Moreover, HDAC6 inhibition was found to diminish the activation of Akt, a downstream kinase involved in the PI3K pathway ( 14 ), and to affect the development of T cells ( 15 ).…”

“…Results from preclinical findings ( 38 ) and a phase I clinical trial show that combining vorinostat and bexarotene can provide clinical relief of pruritus ( 39 ). Other HDACi combinations have been investigated in preclinical and clinical studies ( 40 ) involving the use of interferon-gamma (IFN γ ) ( 41 , 42 ), retinoids ( 43 ), ultraviolet A (UV-A) phototherapy ( 44 ), extracorporeal photopheresis (ECP) ( 45 ), PI3K inhibitors ( 12 , 46 ) the proteasome inhibitor bortezomib ( 47 ), and hypomethylated agents such as azacytidine ( 48 ) ( Figure 1 ). However, these combinations do not show remarkable outcomes.…”

Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group

“…Over the past decade, HDACs have emerged as important drug targets with a broad range of applications, such as treating cancers and central nervous system diseases. [4][5][6][7][8][9] To date, 5 HDAC inhibitors are globally approved (Fig. 1).…”

“…The zinc-dependent HDACs are divided into 4 classes, including class I (HDAC 1, 2, 3, and 8), class IIa (HDAC 4, 5, 7, and 9), class IIb (HDAC6 and 10), and class IV (HDAC11). Over the past decade, HDACs have emerged as important drug targets with a broad range of applications, such as treating cancers and central nervous system diseases [4–9] . To date, 5 HDAC inhibitors are globally approved (Fig.…”