PO.ET09.02 · 实验与分子治疗
PCNA与HDAC抑制剂联合在皮肤T细胞淋巴瘤及其他癌症中的治疗潜力
Therapeutic potential of PCNA and HDAC inhibitor combinations in cutaneous T-cell lymphoma and other cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
AOH1996是一种小分子抑制剂，旨在靶向癌症中增殖细胞核抗原（PCNA）的蛋白结合，先前已证明其可在NCI-60人类肿瘤细胞系筛选中抑制细胞生长，而对非恶性细胞的毒性极小。在AOH1996处理后对磷酸化蛋白进行翻译后修饰特征富集分析的指导下，我们测试了其与组蛋白去乙酰化酶抑制剂（HDACi）贝利司他（belinostat）和伏立诺他（vorinostat）的联合。AOH1996与HDACi联合处理在神经母细胞瘤、乳腺癌、结肠癌和皮肤T细胞淋巴瘤（CTCL）细胞系中显示出协同的生长抑制。一项CRISPR干扰筛选和选择性HDACi研究提示，与AOH1996的协同作用涉及HDAC3和HDAC6。此外，AOH1996与伏立诺他或罗米地辛（romidepsin，二者均经FDA批准用于治疗CTCL）联合，在四种源自CTCL的细胞系中显示出协同的生长抑制。机制研究揭示，用AOH1996和HDACi处理的CTCL细胞中DNA损伤反应增强、细胞周期停滞和凋亡增加。这些发现支持将AOH1996与HDACi联合用于治疗包括CTCL在内的癌症的治疗潜力。
查看英文原文 English abstract
AOH1996, a small molecule inhibitor designed to target protein binding of proliferating cell nuclear antigen (PCNA) in cancer, was previously shown to inhibit cell growth across the NCI-60 human tumor cell line screen with minimal toxicity to nonmalignant cells. Guided by post-translational modification signature enrichment analysis of phosphorylated proteins after AOH1996 treatment, we tested its combination with histone deacetylase inhibitors (HDACi) belinostat and vorinostat. Treatment with AOH1996 and HDACi showed synergistic growth inhibition in neuroblastoma, breast, colon, and cutaneous T-cell lymphoma (CTCL) cell lines. A CRISPR interference screen and selective HDACi studies suggested that the synergy with AOH1996 involved HDAC3 and HDAC6. Furthermore, AOH1996 combined with vorinostat or romidepsin, both FDA-approved for treatment of CTCL, showed synergistic growth inhibition in four cell lines derived from CTCL. Mechanistic studies revealed enhanced DNA damage response, cell cycle arrest, and apoptosis in CTCL cells treated with AOH1996 and HDACi. These findings support the therapeutic potential of combining AOH1996 with HDACi for the treatment of cancers, including CTCL.
利益披露 Disclosure
C. M. Li, None..
R. G. Lingeman, None..
L. Gu, None..
R. J. Hickey, None..
L. H. Malkas, None.