Department of Dermatology and Allergy, Skin Cancer Center Charité (HTCC), Charité-University Medical Center Berlin, Berlin, Germany.
J Invest Dermatol. 2012 Sep;132(9):2263-74. doi: 10.1038/jid.2012.125. Epub 2012 May 3.
Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, whereas cytotoxicity was less pronounced. Both extrinsic and intrinsic apoptosis pathways were activated, as seen by processing of initiator caspases 8 and 9, loss of mitochondrial membrane potential, and cytochrome c release. Characteristically, antiapoptotic mediators such as Mcl-1, XIAP, survivin, and c-FLIP were downregulated. Consistent with its critical function, c-FLIP overexpression resulted in a significant decrease of SAHA-mediated apoptosis. Enhanced sensitivity to TRAIL (TNF-related apoptosis-inducing ligand) and enhanced TRAIL signaling was seen in CTCL cell lines with high sensitivity, whereas cell lines with moderate response were characterized by downregulation of TRAIL-R2 and weaker TRAIL expression. Comparable proapoptotic responses to SAHA and to the combination with TRAIL were seen in ex vivo tumor T cells of CTCL patients. Thus, activation of extrinsic apoptosis pathways, related to c-FLIP downregulation and enhanced TRAIL signaling, appeared as characteristic for CTCL cell responsiveness to SAHA. An improved understanding of the pathways may facilitate its targeted use and the selection of suitable combinations.
丁酸钠（SAHA）已被批准用于治疗皮肤 T 细胞淋巴瘤（CTCL），但其作用机制仍很大程度上难以捉摸。如本文在四种 CTCL 细胞系中所示，细胞活力的丧失与明显的时间和剂量依赖性凋亡诱导相关，而细胞毒性则不太明显。细胞凋亡的外在和内在途径都被激活，表现为起始半胱氨酸蛋白酶 8 和 9 的加工、线粒体膜电位丧失和细胞色素 c 释放。典型地，抗凋亡介质如 Mcl-1、XIAP、survivin 和 c-FLIP 被下调。与它的关键功能一致，c-FLIP 的过表达导致 SAHA 介导的细胞凋亡显著减少。在对 SAHA 高度敏感的 CTCL 细胞系中观察到对 TRAIL（TNF 相关凋亡诱导配体）的敏感性增强和 TRAIL 信号增强，而对 TRAIL-R2 下调和 TRAIL 表达较弱的中等反应细胞系则具有特征。在 CTCL 患者的肿瘤 T 细胞中，对 SAHA 和与 TRAIL 联合治疗的类似促凋亡反应表明，细胞对外源性凋亡途径的激活，与 c-FLIP 的下调和增强的 TRAIL 信号相关，是 CTCL 细胞对 SAHA 反应性的特征。对这些途径的更好理解可能有助于其靶向使用和合适组合的选择。
