Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
J Photochem Photobiol B. 2014 Feb 5;131:104-12. doi: 10.1016/j.jphotobiol.2014.01.009. Epub 2014 Jan 22.
Cutaneous T cell lymphomas (CTCL) represent rare extranodal non-Hodgkin's lymphomas, which are characterised by pleomorphic skin lesions and distinct T-cell markers. CTCL is a relatively benign disease in its early stages, but survival rates decrease significantly with progression. Histone deacetylase inhibitors (HDACi) have recently emerged as a new class of targeted anticancer therapies for CTCL, which have been shown to induce growth inhibition, terminal differentiation and apoptosis in various cancers in vitro and in vivo. In addition to the intrinsic anticancer properties of HDACi, recent studies have demonstrated its ability to synergise with phototherapy. In particular, we examine the therapeutic potential of HDACi in combination with ultraviolet A (UV-A) phototherapy, employing a halogenated DNA minor groove binding ligand called UVASens as a photosensitiser. In vitro studies have demonstrated that UVASens is approximately 1000-fold more potent than current psoralens. The extreme photopotency of UVASens allows the use of lower radiation doses minimising the carcinogenic risks associated with the long-term use of phototherapy. Considering, previous findings using the photosensitiser UVASens and potential synergy of HDACi with phototherapy, it was hypothesised that HDACi will augment photochemotherapy-induced cytotoxicity in CTCL MyLa cells. The findings indicated that combinations of UVASens/UV-A photochemotherapy and HDACi significantly decreased cell viability and increased apoptosis and DNA double-strand breaks in MyLa cells.
皮肤 T 细胞淋巴瘤 (CTCL) 是一种罕见的结外非霍奇金淋巴瘤，其特征为多形性皮肤损伤和独特的 T 细胞标志物。CTCL 在早期阶段是一种相对良性的疾病，但随着病情的进展，生存率显著下降。组蛋白去乙酰化酶抑制剂 (HDACi) 最近成为 CTCL 的一种新型靶向抗癌治疗药物，已证明其在体外和体内能诱导各种癌症的生长抑制、终末分化和凋亡。除了 HDACi 的内在抗癌特性外，最近的研究还表明它能够与光疗协同作用。特别是，我们检查了 HDACi 与紫外线 A (UV-A) 光疗联合使用的治疗潜力，使用一种称为 UVASens 的卤化 DNA 小沟结合配体作为光敏剂。体外研究表明，UVASens 的效力比目前的补骨脂素强约 1000 倍。UVASens 的极端光效允许使用较低的辐射剂量，最大限度地降低与长期光疗相关的致癌风险。鉴于之前使用光敏剂 UVASens 的发现以及 HDACi 与光疗的潜在协同作用，假设 HDACi 将增强 CTCL MyLa 细胞光化学疗法诱导的细胞毒性。研究结果表明，UVASens/UV-A 光化学疗法联合 HDACi 显著降低了 MyLa 细胞的活力，增加了细胞凋亡和 DNA 双链断裂。
