Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases
Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases
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DOI：
10.1007/s00401-006-0082-8
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发表时间：
2006-08-01
影响因子：
12.7
通讯作者：
Siebzehnruebl, Florian A.
中科院分区：
文献类型：
--
作者：
Hoelsken, Annett;Eyuepoglu, Ilker Y.;Siebzehnruebl, Florian A.
患有恶性黑色素瘤的患者的疾病进展通常由转移扩散到脑实质中来确定。因此，全身化疗方案是成功治疗的必要条件。最近，组蛋白脱乙酰酶（HDACi）的抑制剂已显示出显著抑制黑素瘤进展。在此，将小鼠以及人黑素瘤细胞移植到啮齿动物海马切片培养物中，以在器官型脑环境中转化并在显微镜下确认HDACi的有希望的体外化疗倾向。在我们的离体模型中，通过在8天的时间内施用低微摩尔浓度的第二代HDACi MS-275显著抑制肿瘤进展。相比之下，HDACi治疗辛二酰苯胺异羟肟酸是不太有效的离体，虽然这两种化合物是成功的肿瘤细胞单层培养物的治疗。HDACi治疗后细胞周期抑制剂p21（WAF 1）的蛋白水平显著增加，这表明肿瘤细胞的G1期阻滞增强，细胞荧光分析证实。考虑到MS-275穿过血脑屏障的能力，我们的实验模型将苯甲酰胺MS-275鉴定为用于靶向表观遗传染色质调节作为转移性黑色素瘤的全身治疗的有前景的治疗化合物。
Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concentrations of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compounds were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21(WAF1) were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric analysis. Considering the ability of MS-275 to cross the blood-brain barrier, our experimental model identifies the benzamide MS-275 as a promising therapeutic compound for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas.