Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer.
Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer.
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DOI：
10.1093/carcin/bgt123
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发表时间：
2013-08
期刊：
影响因子：
4.7
通讯作者：
N. Shamaladevi;D. Lyn;K. Shaaban;Lei Zhang;Susana Villate;J. Rohr;B. Lokeshwar
中科院分区：
文献类型：
--
作者：
N. Shamaladevi;D. Lyn;K. Shaaban;Lei Zhang;Susana Villate;J. Rohr;B. Lokeshwar
雄激素受体（AR）信号转导的沉默是治疗前列腺癌（CaP）的一种特异而有效的机制。在这项研究中，分离和表征的化合物的芳香浆果的Pimenta dioica（多香果），沉默AR。在CaP细胞上测试了多香果水提取物（AAE）和从提取物纯化的化合物的潜在抗肿瘤活性。AAE抑制肿瘤细胞增殖和集落形成（50%生长抑制<40 - 85 µ g/ml），但不抑制静止正常成纤维细胞或非致瘤性前列腺细胞的活力。在肿瘤细胞中，AAE抑制细胞周期进展于G1/S，诱导凋亡或自噬。凋亡是通过半胱天冬酶依赖的聚（ADP核糖）聚合酶切割。非半胱天冬酶依赖性、凋亡诱导因子介导的凋亡机制导致去势抵抗性AR阳性或AR阴性CaP细胞（如CWR22RV1、PC-3或DU145细胞）的细胞死亡。AAE处理降低了AR阳性细胞中AR信使RNA（mRNA）、蛋白质的水平，并沉默了AR活性。AR耗竭是由于AR启动子活性和mRNA稳定性的抑制。在经口或腹腔途径给予AAE的LNCaP荷瘤小鼠中观察到肿瘤生长延迟（~55%），但无可测量的全身毒性。来自AAE处理的小鼠的LNCaP肿瘤组织显示细胞凋亡增加是AAE抗肿瘤活性的潜在机制。通过多步高效液相色谱分离、质谱和核磁共振谱确定了AAE中活性成分的化学成分。化合物丁香酚5-O-β-（6'-没食子酰基吡喃葡萄糖苷）或Eriicifolin（EF）具有抗增殖、促凋亡和抗AR转录活性。这些结果表明AAE和EF对前列腺癌的潜在用途。
Silencing of androgen receptor (AR) signaling is a specific and effective mechanism to cure cancer of the prostate (CaP). In this study, the isolation and characterization of a compound from the aromatic berries of Pimenta dioica (allspice) that silences AR is presented. Potential antitumor activities of an aqueous allspice extract (AAE) and a compound purified from the extract were tested on CaP cells. AAE inhibited tumor cell proliferation and colony formation (50% growth inhibition ∼40-85 µg/ml) but not the viability of quiescent normal fibroblasts or non-tumorigenic prostate cells. In tumor cells, AAE inhibited cell cycle progression at G1/S, induced apoptosis or autophagy. Apoptosis was by caspase-dependent poly (ADP ribose) polymerase cleavage. A caspase-independent, apoptosis-inducing factor-mediated mechanism of apoptosis caused cell death in castration-resistant AR-positive or AR-negative CaP cells, such as CWR22RV1, PC-3 or DU145 cells. Treatment with AAE decreased the levels of AR messenger RNA (mRNA), protein and silenced AR activity in AR-positive cells. AR depletion was due to inhibition of AR promoter activity and mRNA stability. Delayed tumor growth (~55%) without measurable systemic toxicity was observed in LNCaP tumor-bearing mice treated with AAE by oral or intraperitoneal routes. LNCaP tumor tissues from AAE-treated mice revealed increased apoptosis as a potential mechanism of antitumor activity of AAE. The chemical identity of bioactive compound in AAE was established through multistep high-performance liquid chromatography fractionation, mass and Nuclear Magnetic Resonance spectroscopies. The compound, eugenol 5-O-β-(6'-galloylglucopyranoside) or ericifolin (EF), showed antiproliferative, pro-apoptosis and anti-AR transcription activities. These results demonstrate a potential use of AAE and EF against prostate cancer.