Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
Mol Cancer Ther. 2017 Apr;16(4):649-661. doi: 10.1158/1535-7163.MCT-16-0749. Epub 2017 Jan 23.
T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). , romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)-dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. .
T 细胞淋巴母细胞性恶性肿瘤（TCLM）需要新的、更有效的治疗方法。组蛋白去乙酰化酶（HDAC）抑制剂罗米地辛和合成细胞毒性维甲酸芬维 A 酯均作为单一药物在 T 细胞淋巴瘤中取得了持久的临床缓解。我们研究了这两种药物联合应用于 TCLM 的潜力。我们在 15 种 TCLM 细胞系中证明了罗米地辛和芬维 A 酯在临床可达到的浓度下具有细胞毒性协同作用，而这些浓度对非恶性细胞（成纤维细胞和血液单核细胞）没有细胞毒性。, 罗米地辛+芬维 A 酯+酮康唑（通过抑制芬维 A 酯代谢增强芬维 A 酯的暴露）在皮下和播散性 TCLM 异种移植模型中的活性大于单药罗米地辛或芬维 A 酯+酮康唑。芬维 A 酯+罗米地辛导致活性氧物种（ROS）依赖性促凋亡蛋白（Bim、tBid、Bax 和 Bak）增加、细胞凋亡和 HDAC 酶活性抑制，从而协同增加组蛋白乙酰化。抗氧化剂（维生素 C 或 E）可阻断芬维 A 酯+罗米地辛的协同细胞毒性、细胞凋亡和组蛋白乙酰化。罗米地辛+芬维 A 酯通过 ROS 激活 p38 和 JNK，并且 p38 和 JNK1 的敲低显著降低了协同细胞毒性。罗米地辛+芬维 A 酯还对 B 淋巴细胞恶性肿瘤细胞系具有协同细胞毒性，但不会增加 ROS、组蛋白乙酰化、p38+JNK 的激活或非恶性细胞的细胞毒性。罗米地辛+芬维 A 酯通过一种新的分子机制在 TCLM 的临床前模型中实现了协同作用，但在非恶性细胞中没有。这些数据支持在复发和难治性 TCLM 中进行罗米地辛+芬维 A 酯的临床试验。
