Effectiveness of the histone deacetylase inhibitor (S)-2 against LNCaP and PC3 human prostate cancer cells.
Effectiveness of the histone deacetylase inhibitor (S)-2 against LNCaP and PC3 human prostate cancer cells.
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DOI：
10.1371/journal.pone.0058267
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Paoletti F
中科院分区：
文献类型：
--
作者：
Laurenzana A;Balliu M;Cellai C;Romanelli MN;Paoletti F
组蛋白去乙酰化酶抑制剂（HDACi）代表一类具有抗癌特性的有前途的表观遗传剂。在这里，我们报告了（S）-2，一种新的基于异羟肟酸的HDACi，以前被证明对急性髓性白血病细胞有效，也是人前列腺LNCaP和PC 3癌细胞凋亡/分化的有效诱导剂。在LNCaP细胞中，（S）-2能够触发H3/H4组蛋白乙酰化，H2 AX磷酸化作为DNA损伤的标志物，并产生G 0/G1细胞周期阻滞。一致地，（S）-2导致LNCaP细胞中蛋白质和mRNA p21水平的表达增强，但与SAHA相反，在正常的非致瘤性前列腺PNT 1A细胞中没有。机制研究表明，（S）-2-诱导的LNCaP细胞凋亡的发展，通过切割前半胱天冬酶9和3和聚（ADP-核糖）-聚合酶伴随着线粒体膜电位的剂量依赖性损失。事实上，加入泛半胱天冬酶抑制剂Z-VAD-favorite大大减少了药物介导的细胞凋亡，而抗氧化剂N-乙酰半胱氨酸几乎无效。重要的是，用LNCaP细胞异种移植的裸鼠的初步数据显示，（S）-2促使肿瘤体积减小和癌细胞内H2 AX磷酸化增加。此外，高转移性前列腺癌PC 3细胞也对（S）-2敏感，其：i）诱导生长停滞和中度凋亡; ii）引导细胞朝向分化和中性脂质积累; iii）通过降低MMP-9活性的量和上调TIMP-1表达来降低细胞侵袭潜力;和iv）抑制细胞运动性和通过基质胶的迁移。总体而言，（S）-2已被证明是能够诱导LNCaP和PC 3前列腺癌细胞的生长停滞、细胞死亡和/或分化的强大HDACi，并且由于其低毒性和体内功效，也可能具有支持常规前列腺癌治疗的临床意义。
Histone deacetylase inhibitors (HDACi) represent a promising class of epigenetic agents with anticancer properties. Here, we report that (S)-2, a novel hydroxamate-based HDACi, shown previously to be effective against acute myeloid leukemia cells, was also a potent inducer of apoptosis/differentiation in human prostate LNCaP and PC3 cancer cells. In LNCaP cells (S)-2 was capable of triggering H3/H4 histone acetylation, H2AX phosphorylation as a marker of DNA damage and producing G0/G1 cell cycle arrest. Consistently, (S)-2 led to enhanced expression of both the protein and mRNA p21 levels in LNCaP cells but, contrary to SAHA, not in normal non-tumorigenic prostate PNT1A cells. Mechanistic studies demonstrated that (S)-2-induced apoptosis in LNCaP cells developed through the cleavage of pro-caspase 9 and 3 and of poly(ADP-ribose)-polymerase accompanied by the dose-dependent loss of mitochondrial membrane potential. Indeed, the addition of the pan-caspase inhibitor Z-VAD-fmk greatly reduced drug-mediated apoptosis while the antioxidant N-acetyl-cysteine was virtually ineffective. Importantly, preliminary data with nude mice xenografted with LNCaP cells showed that (S)-2 prompted a decrease in the tumor volume and an increase in H2AX phosphorylation within the cancer cells. Moreover, the highly metastatic prostate cancer PC3 cells were also sensitive to (S)-2 that: i) induced growth arrest and moderate apoptosis; ii) steered cells towards differentiation and neutral lipid accumulation; iii) reduced cell invasiveness potential by decreasing the amount of MMP-9 activity and up-regulating TIMP-1 expression; and iv) inhibited cell motility and migration through the Matrigel. Overall, (S)-2 has proven to be a powerful HDACi capable of inducing growth arrest, cell death and/or differentiation of LNCaP and PC3 prostate cancer cells and, due to its low toxicity and efficacy in vivo, might also be of clinical interest to support conventional prostate cancer therapy.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1111/j.1349-7006.2001.tb02153.x
发表时间：
2001-12
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Choi JH;Kwon HJ;Yoon BI;Kim JH;Han SU;Joo HJ;Kim DY
通讯作者：
Kim DY
影响因子：
6.4
作者：
Kawai, H;Li, HC;Avraham, HK
通讯作者：
Avraham, HK
影响因子：
11.2
作者：
Geng, Ling;Cuneo, Kyle C.;Hallahan, Dennis E.
通讯作者：
Hallahan, Dennis E.
影响因子：
2.8
作者：
Halkidou, K;Gaughan, L;Robson, CN
通讯作者：
Robson, CN