Combination Phototherapy with a Histone Deacetylase Inhibitor and a Potent DNA-Binding Bibenzimidazole: Effects in Haematological Cell Lines

Annabelle L Rodd ,Katherine Ververis,Tom C Karagiannis

doi:10.1155/2012/405327

Abstract

Current treatment for cutaneous T-cell lymphoma includes phototherapy, which involves either the use of narrowband ultraviolet B light or UVA in combination with a psoralen photosensitiser. Therapy typically involves administration of the photosensitiser followed by topical exposure to UVA. A different approach is extracorporeal photopheresis, an ex vivo strategy which is used for more advanced stages of disease. Further, histone deacetylase inhibitors are emerging as potent anticancer agents with suberoylanilide hydroxamic acid and depsipeptide, having received FDA approval for the treatment of cutaneous T-cell lymphoma. We have developed UVASens, an extremely potent, DNA minor groove-binding UVA sensitizer for potential use in phototherapy. We have previously demonstrated the extreme photopotency of UVASens in human erythroleukemic K562 cells. Here we have extended those studies by investigating the photopotency of UVASens in four haematological cell lines, namely, K562, T-cell leukaemic CEM-CCRF, P-glycoprotein overexpressing R100, and transformed B-lymphoblastoid cell lines (LCL) cells. In addition, we investigated the effects of suberoylanilide hydroxamic acid in combination with UVASens. Using γH2AX as the endpoint, our findings indicate that UVASens-induced phototoxicity in all four of the haematological cell lines. The addition of suberoylanilide hydroxamic acid augmented the photopotency of UVASens highlighting the potential clinical applicability of combination therapies.

Highlights

Cutaneous T-cell lymphoma (CTCL) describes a heterogenous series of extranodal non-Hodgkin T-cell lymphomas that primarily appear in the skin [1, 2]
Human chronic myelogenous leukemia K562 cells [25] and the lymphoblastoid cell line (LCL) were maintained in completeRoyal Park Memorial Institute (RPMI) 1640 medium supplemented with 20 mmol/L HEPES, 10% (v/v) fetal bovine serum (FBS), 2 mmol/glutamine, and 80 gentamicin units (GIBCO-Invitrogen)
Our findings showed that over 24 hours SAHA induces the accumulation of hyperacetylated histones—H2B, H3, and H4 in all four haematological cell lines (Figure 2(b))

Summary

Introduction

Cutaneous T-cell lymphoma (CTCL) describes a heterogenous series of extranodal non-Hodgkin T-cell lymphomas that primarily appear in the skin [1, 2]. CTCL is characterised by an initial influx of T-cells of the CD4 phenotype in the skin, which have the propensity to home and accumulate in the blood and lymph nodes as the disease develops [2,3,4]. The two most common subtypes of CTCL include mycosis fungoides (MF), generally a low-grade lymphoma characterised by skin manifestations and the erythrodermic version Sezary syndrome. Sezary syndrome is an aggressive leukemic form of the disease identifiable by diffuse skin involvement (erythroderma), lymphadenopathy, and the presence of abnormal lymphoid cells circulating in the blood [5, 6]. While a plethora of treatments are available for CTCL, most remain palliative, and prolonged remissions or cures are rare for advanced stages of the disease

Methods

Results

Conclusion