前列腺癌就是发生于男性前列腺组织中的恶性肿瘤，是前列腺腺泡细胞异常无序生长的结果。前列腺癌的发病率具有明显的地理和种族差异。在欧美等发达国家和地区，它是男性最常见的恶性肿瘤，其死亡率居各种癌症的第二位；在亚洲，其发病率低于西方国家，但近年来呈迅速上升趋势。
雄激素受体在前列腺癌的发生发展过程中发挥重要作用，去势治疗（ADT）的主要靶标就是抑制前列腺癌患者体内雄激素受体。但临床上该种治疗方法往往以失败告终，其原因主要是前列腺癌患者受体内雄激素受体被再次激活。在ADT治疗过程中，由于p300和CPB的存在，前列腺癌细胞能保持活性存活下来。
最近，Cancer Research杂志上刊登的一项关于咖喱中姜黄素的临床前研究证实：姜黄素对去势治疗无效的前列腺癌患者的雄激素剥夺治疗中，有抑制肿瘤生长功效。
来自托马斯-杰斐逊大学的癌症生物学教授--Karen-Knudsen博士等研究人员发现：姜黄素能抑制两种降低ADT治疗功效的核受体活化剂--P300和CPB。
研究人员发现姜黄素能提高ADT的治疗效果，与单独接受ADT组相比，ADT联合姜黄素能更显著减少前列腺癌患者体内癌细胞数量。为了验证之一发现，科研人员用动物实验模拟临床治疗，将小鼠（接受过ADT治疗）随机分成姜黄素处理组和对照组两组。
结果表明用姜黄素处理的小鼠，体内肿瘤细胞的生长和数量有明显下降。说明姜黄素能有效地抑制去势治疗无效的前列腺癌细胞的生长。研究人员希望姜黄素或许能成为一种很有开发价值的抗肿瘤药物。(生物谷 Bioon.com)
doi:10.1158/0008-5472.CAN-11-0943
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PMID:
Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression
Supriya A. Shah1, Shikha Prasad2, and Karen E. Knudsen3,*
Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g. GATA2 and FOXA1). Thus, a major current emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by illustrated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results demonstrate the combinatorial impact of targeting AR and histone modification in prostate cancer, setting the stage for further development of curcumin as a novel agent to target AR signaling.
