前列腺癌就是發(fā)生于男性前列腺組織中的惡性腫瘤，是前列腺腺泡細(xì)胞異常無(wú)序生長(zhǎng)的結(jié)果,。前列腺癌的發(fā)病率具有明顯的地理和種族差異,。在歐美等發(fā)達(dá)國(guó)家和地區(qū),，它是男性最常見(jiàn)的惡性腫瘤，其死亡率居各種癌癥的第二位,；在亞洲,，其發(fā)病率低于西方國(guó)家，但近年來(lái)呈迅速上升趨勢(shì),。
雄激素受體在前列腺癌的發(fā)生發(fā)展過(guò)程中發(fā)揮重要作用,，去勢(shì)治療（ADT）的主要靶標(biāo)就是抑制前列腺癌患者體內(nèi)雄激素受體。但臨床上該種治療方法往往以失敗告終,，其原因主要是前列腺癌患者受體內(nèi)雄激素受體被再次激活,。在ADT治療過(guò)程中，由于p300和CPB的存在,，前列腺癌細(xì)胞能保持活性存活下來(lái),。
最近，Cancer Research雜志上刊登的一項(xiàng)關(guān)于咖喱中姜黃素的臨床前研究證實(shí)：姜黃素對(duì)去勢(shì)治療無(wú)效的前列腺癌患者的雄激素剝奪治療中,，有抑制腫瘤生長(zhǎng)功效,。
來(lái)自托馬斯-杰斐遜大學(xué)的癌癥生物學(xué)教授--Karen-Knudsen博士等研究人員發(fā)現(xiàn)：姜黃素能抑制兩種降低ADT治療功效的核受體活化劑--P300和CPB。
研究人員發(fā)現(xiàn)姜黃素能提高ADT的治療效果,，與單獨(dú)接受ADT組相比,，ADT聯(lián)合姜黃素能更顯著減少前列腺癌患者體內(nèi)癌細(xì)胞數(shù)量,。為了驗(yàn)證之一發(fā)現(xiàn)，科研人員用動(dòng)物實(shí)驗(yàn)?zāi)M臨床治療,，將小鼠（接受過(guò)ADT治療）隨機(jī)分成姜黃素處理組和對(duì)照組兩組,。
結(jié)果表明用姜黃素處理的小鼠，體內(nèi)腫瘤細(xì)胞的生長(zhǎng)和數(shù)量有明顯下降,。說(shuō)明姜黃素能有效地抑制去勢(shì)治療無(wú)效的前列腺癌細(xì)胞的生長(zhǎng),。研究人員希望姜黃素或許能成為一種很有開(kāi)發(fā)價(jià)值的抗腫瘤藥物。(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.
