ITF2357 是一种新型组蛋白脱乙酰酶抑制剂，对人多发性骨髓瘤细胞具有显着的凋亡活性。,Blood

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ITF2357 是一种新型组蛋白脱乙酰酶抑制剂，对人多发性骨髓瘤细胞具有显着的凋亡活性。
Blood ( IF 21.0 ) Pub Date : 2007-11-16 , DOI: 10.1182/blood.v110.11.4791.4791
Michael Kline ₁ , Kathleen A. Donovan ₁ , John A. Lust ₁

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我们评估了一种新型异羟肟酸衍生的组蛋白去乙酰化酶 (HDAC) 抑制剂 ITF2357 促进多发性骨髓瘤 (MM) 细胞死亡的功效。HDAC 抑制剂可促进组蛋白过度乙酰化并增加基因表达，已被评估为对抗恶性肿瘤的候选药物，因为它们会影响与增殖、分化和存活相关的基因的表达。通过西方分析，将 MM 细胞系暴露于 1 微摩尔 ITF2357 导致组蛋白乙酰化水平在 4 小时和 8 小时显着增加。亚微摩尔浓度的 ITF2357 促进了 MM 细胞系中时间和浓度依赖性细胞死亡。使用 500 nM ITF2357，在体内可能达到的浓度，KAS-6/1 IL-6 依赖性骨髓瘤细胞的生存力在 24 小时时降至对照的 28%，在 48 小时时降至对照的 2%（图 1）。相比之下，正常 PBMC 的活力在 24 小时时为 100%，在 48 小时时为 80%（图 2）。发现 U266 和 8226 骨髓瘤细胞以类似的方式对 ITF-2357 敏感，而 U266 最不敏感。如使用膜联蛋白 V/碘化丙啶染色测量的那样，细胞死亡通过细胞凋亡进行。ITF 2357 在抑制基质细胞 IL-6 产生方面优于辛二酰苯胺异羟肟酸 (SAHA)。48 小时后，使用 IL-1beta（10 pg/ml）刺激骨髓基质细胞 IL-6 的产生（105 ng/ml）。ITF2357: 48 小时后基质细胞 IL-6 产生的浓度如下 - 10 nM：78 ng/ml；100 nM：79 纳克/毫升；1000纳米；32 纳克/毫升。与无药物对照相比，类似浓度的 SAHA 没有显示基质细胞 IL-6 产生的显着降低。总之，ITF2357 诱导显着的骨髓瘤细胞凋亡并能抑制基质细胞 IL-6 的产生。它代表了 MM 临床试验的有吸引力的治疗候选者。![图][1] 图 ![图][1] 图[1]：待定：是

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ITF2357, a Novel Histone Deacetylase Inhibitor, Demonstrates Significant Apoptotic Activity Against Human Multiple Myeloma Cells.

We have evaluated the efficacy of a novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor, ITF2357, to promote cell death in multiple myeloma (MM) cells. HDAC inhibitors, which promote histone hyperacetylation and increase gene expression, have been evaluated as candidate agents for combating malignancies because they impact the expression of genes related to proliferation, differentiation, and survival. Exposure of MM cell lines to 1 micromolar ITF2357 led to dramatically increased levels of histone acetylation at 4 hours and 8 hours by Western analysis. Sub-micromolar concentrations of ITF2357 promoted time- and concentration-dependent cell death in MM cell lines. Using 500 nM ITF2357, a concentration potentially achievable in vivo, viability of KAS-6/1 IL-6 dependent myeloma cells was reduced to 28% of control at 24 hrs and 2% of control at 48 hours (Figure 1). In contrast, viability of normal PBMCs was 100% at 24 hours and 80% at 48 hours (Figure 2). U266 and 8226 myeloma cells were found to be sensitive to ITF-2357 in a similar fashion with U266 being least sensitive. Cell death proceeded via apoptosis as measured using Annexin V/propidium iodide staining. ITF 2357 was superior to suberoylanilide hydroxamic acid (SAHA) at inhibition of stromal cell IL-6 production. IL-1beta (10 pg/ml) was used to stimulate bone marrow stromal cell IL-6 production (105 ng/ml) after 48 hours. Concentration of ITF2357:Stromal Cell IL-6 production after 48 hours were as follows - 10 nM: 78 ng/ml; 100 nM: 79 ng/ml; 1000 nM; 32 ng/ml. SAHA at similar concentrations showed no significant decrease in stromal cell IL-6 production compared with the no drug control. In summary, ITF2357 induces significant myeloma cell apoptosis and can inhibit stromal cell IL-6 production. It represents an attractive therapeutic candidate for MM clinical trials. ![Figure][1] Figure ![Figure][1] Figure [1]: pending:yes

更新日期：2007-11-16

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