Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.
Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.
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DOI：
10.1158/1078-0432.ccr-11-0431
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Lee P
中科院分区：
文献类型：
--
作者：
Li Y;Ligr M;McCarron JP;Daniels G;Zhang D;Zhao X;Ye F;Wang J;Liu X;Osman I;Mencher SK;Lepor H;Wang LG;Ferrari A;Lee P
迫切需要开发副作用最小的新型有效治疗剂来治疗前列腺癌。靛玉红是传统中草药青黛中发现的一种活性分子，数十年来一直用于治疗白血病。然而，Natura-alpha（一种靛玉红衍生物）的抗癌特性尚未在实体瘤（特别是前列腺癌）中得到充分研究。用或不用 Natura-alpha 处理人前列腺癌细胞系，然后测量细胞生长和侵袭测定。在裸鼠肿瘤异种移植模型以及晚期激素难治性转移性前列腺癌患者中检查了 Natura-alpha 的抗肿瘤作用。使用蛋白质组通路阵列分析 (PPAA) 对异种移植物分析 Natura-alpha 靶向的信号网络蛋白。 Natura-alpha 抑制雄激素依赖性 (LNCaP) 和雄激素非依赖性 (LNCaP-AI、PC-3 和 DU145) 前列腺癌细胞的生长，IC50 在 4 至 10 μm 之间，还抑制雄激素非依赖性前列腺癌细胞的侵袭。其抗肿瘤作用在体内雄激素依赖性和非依赖性裸鼠肿瘤异种移植模型中的肿瘤缩小以及激素难治性转移性前列腺癌患者的肿瘤体积缩小方面进一步明显。 PPAA 揭示 Natura-alpha 对前列腺癌的抗增殖和抗侵袭活性可能主要是通过下调 Forkhead box M1 (FOXM1) 蛋白实现的。 FOXM1 的强制过度表达在很大程度上逆转了 Natura-alpha 的抑制作用。 Natura-alpha 可以作为一种新型有效的治疗剂，用于治疗激素敏感型和激素难治性前列腺癌，且副作用最小。
The development of new effective therapeutic agents with minimal side effects for prostate cancer treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine – Qing Dai (Indigo Naturalis), has been used to treat leukemia for decades. However, the anti-cancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in prostate cancer. Human prostate cancer cell lines were treated with or without Natura-alpha followed by cell growth and invasion assays measured. The anti-tumor effects of Natura-alpha were examined in nude mice tumor xenograft models, as well as in a patient with advanced hormone refractory metastatic prostate cancer. Signal network proteins targeted by Natura-alpha were analyzed using Proteomic Pathway Array Analysis (PPAA) on xenografts. Natura-alpha inhibited the growth of both androgen-dependent (LNCaP), and androgen-independent (LNCaP-AI, PC-3, and DU145) prostate cancer cells with IC50 between 4 to 10 Μm, also inhibits invasion of androgen-independent prostate cancer cells. Its anti-tumor effects were further evident in vivo tumor reduction in androgen-dependent and -independent nude mice tumor xenograft models as well as reduced tumor volume in the patient with hormone refractory metastatic prostate cancer. PPAA revealed that anti-proliferative and anti-invasive activities of Natura-alpha on prostate cancer might primarily be through its down-regulation of Forkhead box M1 (FOXM1) protein. Forced over-expression of FOXM1 largely reversed the inhibition by Natura-alpha. Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone sensitive and hormone refractory prostate cancer with minimal side effects.