HDAC-inhibitor (S)-8 disrupts HDAC6-PP1 complex prompting A375 melanoma cell growth arrest and apoptosis.
HDAC-inhibitor (S)-8 disrupts HDAC6-PP1 complex prompting A375 melanoma cell growth arrest and apoptosis.
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DOI：
10.1111/jcmm.12345
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发表时间：
2015-01
影响因子：
5.3
通讯作者：
Paoletti F
中科院分区：
文献类型：
--
作者：
Balliu M;Guandalini L;Romanelli MN;D'Amico M;Paoletti F
组蛋白脱乙酰酶抑制剂（HDACi）是能够在不同肿瘤细胞类型中诱导生长停滞和凋亡的药剂。以前，我们报道了一系列新的HDACi通过杂交SAHA或oxamflatin与1，4-苯并二氮杂卓。这些杂合物中的一些被证明对血液和实体癌细胞有效，并且最重要的是，化合物（S）-8因其在各种生物系统中的活性而出现。在此，我们通过使用正常PIG 1黑素细胞作为对照，描述了（S）-8对高转移性人A375黑色素瘤细胞的有效性。(S)-8提示：组蛋白H3/H4和α-微管蛋白的乙酰化;通过升高p21和低聚磷酸化RB水平使G 0/G1和G2/M细胞周期阻滞;涉及PARP和caspase 9裂解的凋亡，BAD蛋白增加和细胞色素c释放;伤口愈合试验结果显示细胞运动性、侵袭性和促血管生成潜力降低，MMP-2和VEGF-A/VEGF-R2下调，此外，TIMP-1/TIMP-2上调;以及黑色素和中性脂质的细胞内积累。泛半胱天冬酶抑制剂Z-VAD-fetamine，而不是抗氧化剂N-乙酰半胱氨酸，对比这些事件。从机制上讲，（S）-8可以破坏A375细胞中的细胞质HDAC 6-蛋白磷酸酶1（PP 1）复合物，从而释放活性PP 1，使AKT去磷酸化并阻断其下游促生存信号传导。该观点与通过以下获得的结果一致：用Calyculin A抑制PP 1;使用PP 1活性受损的PPP 1 R2转染细胞;监测药物诱导的HDAC 6-PP 1复合物重新改组;以及用特异性siRNA废除HDAC 6表达。总而言之，（S）-8被证明对黑色素瘤A375细胞非常有效，但对正常黑素细胞无效，并且对正常小鼠安全，因此为治疗这种侵袭性恶性肿瘤提供了有吸引力的临床前景。
Histone deacetylase inhibitors (HDACi) are agents capable of inducing growth arrest and apoptosis in different tumour cell types. Previously, we reported a series of novel HDACi obtained by hybridizing SAHA or oxamflatin with 1,4-benzodiazepines. Some of these hybrids proved effective against haematological and solid cancer cells and, above all, compound (S)-8 has emerged for its activities in various biological systems. Here, we describe the effectiveness of (S)-8 against highly metastatic human A375 melanoma cells by using normal PIG1 melanocytes as control. (S)-8 prompted: acetylation of histones H3/H4 and α-tubulin; G0/G1 and G2/M cell cycle arrest by rising p21 and hypophos-phorylated RB levels; apoptosis involving the cleavage of PARP and caspase 9, BAD protein augmentation and cytochrome c release; decrease in cell motility, invasiveness and pro-angiogenic potential as shown by results of wound-healing assay, down-regulation of MMP-2 and VEGF-A/VEGF-R2, besides TIMP-1/TIMP-2 up-regulation; and also intracellular accumulation of melanin and neutral lipids. The pan-caspase inhibitor Z-VAD-fmk, but not the antioxidant N-acetyl-cysteine, contrasted these events. Mechanistically, (S)-8 allows the disruption of cytoplasmic HDAC6-protein phosphatase 1 (PP1) complex in A375 cells thus releasing the active PP1 that dephosphorylates AKT and blocks its downstream pro-survival signalling. This view is consistent with results obtained by: inhibiting PP1 with Calyculin A; using PPP1R2-transfected cells with impaired PP1 activity; monitoring drug-induced HDAC6-PP1 complex re-shuffling; and, abrogating HDAC6 expression with specific siRNA. Altogether, (S)-8 proved very effective against melanoma A375 cells, but not normal melanocytes, and safe to normal mice thus offering attractive clinical prospects for treating this aggressive malignancy.
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