Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer (Retracted Article)
Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer (Retracted Article)
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DOI：
10.1158/1078-0432.ccr-06-0429
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发表时间：
2006-09-01
影响因子：
11.5
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Kulp, Samuel K.;Chen, Chang-Shi;Chen, Ching-Shih
目的：为了评估一种新的苯丁酸衍生的组蛋白脱乙酰酶（HDAC）抑制剂（S）-HDAC-42与辛二酰苯胺异羟肟酸（SAHA）在体外和体内人前列腺癌模型中的抗肿瘤作用，实验设计：在PC-3、DIJ-145或LNCaP人前列腺癌细胞系中评估（S）-HDAC-42和SAHA的体外作用。评估细胞活力、凋亡和HDAC抑制的指标。通过免疫印迹法测定对Akt和Bcl-2及凋亡抑制蛋白家族成员的影响。免疫功能低下小鼠，皮下接种将PC-3异种移植肿瘤用（S）-HDAC-42（50 mg/kg q.o.d.或25 mg/kg q.d.）或SAHA（50 mg/kg每日一次）28天。体内终点包括肿瘤体积和组蛋白乙酰化、磷酸化Akt状态和Bcl-xL和survivin.Results的蛋白水平的肿瘤内变化：（S）-HDAC-42在抑制用亚微摩尔IC 50值评估的所有细胞系的活力方面比SAHA更有效。相对于SAHA，（S）-HDAC-42表现出明显上级的致瘤效力，并在PC-3细胞中引起磷酸化Akt、Bcl-xL和存活素的显著更大的降低。在用25和50 mg/kg的（S）-HDAC-42处理后，PC-3肿瘤异种移植物的生长分别被抑制52%和67%，而50 mg/kg的SAHA抑制生长31%。结论：（S）-HDAC-42是一种有效的口服生物利用度高的HDAC抑制剂，也是调节癌细胞存活的多个方面的靶点，在前列腺癌化疗中可能具有临床价值，值得进一步研究。
Purpose: To assess the antitumor effects of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42, vis-a-vis suberoylanilide hydroxamic acid (SAHA) in in vitro and in vivo models of human prostate cancer.Experimental Design: The in vitro effects of (S) -HDAC-42 and SAHA were evaluated in PC-3, DIJ-145, or LNCaP human prostate cancer cell lines. Cell viability, apoptosis, and indicators of HDAC inhibition were assessed. Effects on Akt and members of the Bcl-2 and inhibitor of apoptosis protein families were determined by immunoblotting. Immunocompromised mice bearing established s.c. PC-3 xenograft tumors were treated orally with (S)-HDAC-42 (50 mg/kg q.o.d. or 25 mg/kg q.d.) or SAHA (50 mg/kg q.d.) for 28 days. In vivo end points included tumor volumes and intratumoral changes in histone acetylation, phospho-Akt status, and protein levels of Bcl-xL and survivin.Results: (S)-HDAC-42 was more potent than SAHA in suppressing the viability of all cell lines evaluated with submicromolar IC50 values. Relative to SAHA, (S) -HDAC-42 exhibited distinctly superior apoptogenic potency, and caused markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. The growth of PC-3 tumor xenografts was suppressed by 52% and 67% after treatment with (S)-HDAC-42 at 25 and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppressed growth by 31%. Intratumoral levels of phospho-Akt and Bcl-xL were markedly reduced in (S)-HDAC-42-treated mice, in contrast to mice treated with SAHA.Conclusions: (S)-HDAC-42 is a potent orally bioavailable inhibitor of HDAC, as well as targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy and warrants further investigation in this regard.