Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University; State Key Laboratory of Ophthalmology, Sun Yat-Sen University Zhongshan Ophthalmic Center, Guangzhou, China.
Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Cancer Lett. 2017 Aug 1;400:47-60. doi: 10.1016/j.canlet.2017.04.028. Epub 2017 Apr 26.
Uveal melanoma (UM) is the most common intraocular malignant neoplasm in adults. Despite the availability of enucleation, radiation and chemotherapy, the prognosis of patients with metastasis remains poor. Therefore, novel effective therapies for patients with metastatic UM are urgently needed. In the present study, we demonstrated that JSL-1, a novel HDAC inhibitor, effectively inhibited the proliferation. JSL-1 induced apoptosis with increased expression of proapoptotic BH3-only protein BIM in UM cells. JSL-1 suppressed migration and invasion of UM cells with MMP-2 decreased. Furthermore, JSL-1 blocked the canonical Wnt/β-catenin pathway, impaired self-renewal capacity and decreased percentage of ALDH cells, thereby reflecting elimination of UM cancer stem-like cells (CSCs) which are believed seeds of metastasis. Importantly, JSL-1 potently inhibited the growth of uveal melanoma xenograft in NOD-SCID mice. These results suggested that JSL-1 may be a promising therapeutic agent for UM.
葡萄膜黑色素瘤（UM）是成年人中最常见的眼内恶性肿瘤。尽管有眼球摘除术、放疗和化疗，但转移性患者的预后仍然很差。因此，迫切需要为转移性 UM 患者提供新的有效治疗方法。在本研究中，我们证明了新型 HDAC 抑制剂 JSL-1 可有效抑制增殖。JSL-1 通过增加促凋亡 BH3 仅蛋白 BIM 的表达诱导 UM 细胞凋亡。JSL-1 抑制 UM 细胞的迁移和侵袭，同时 MMP-2 减少。此外，JSL-1 阻断了经典的 Wnt/β-catenin 通路，损害了自我更新能力并降低了 ALDH 细胞的比例，从而反映了 UM 癌症干细胞样细胞（CSC）的消除，这些细胞被认为是转移的种子。重要的是，JSL-1 可有效抑制 NOD-SCID 小鼠异种移植的葡萄膜黑色素瘤生长。这些结果表明，JSL-1 可能是一种有前途的 UM 治疗药物。
