The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer.
The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer.
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DOI：
10.1038/sj.bjc.6604938
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发表时间：
2009-03-24
影响因子：
8.8
通讯作者：
Calvo, A.
中科院分区：
文献类型：
--
作者：
Diaz, R.;Nguewa, P. A.;Diaz-Gonzalez, J. A.;Hamel, E.;Gonzalez-Moreno, O.;Catena, R.;Serrano, D.;Redrado, M.;Sherris, D.;Calvo, A.
放射治疗（RT）是局部前列腺癌的常见治疗方法，但可能会导致严重的副作用。RT的治疗效果可以通过靶向参与细胞存活的特定途径的药理学化合物来增强。这将使用较低剂量的RT引起类似的治疗反应，从而减少副作用。本研究描述了新型Akt抑制剂8-（1-羟基-乙基）-2-甲氧基-3-（4-甲氧基-苄氧基）-苯并[c]色烯-6-酮（Palomid 529或P529）的抗肿瘤活性以及其在前列腺癌模型中降低辐射激活的磷酸化Akt（p-Akt）信号传导的能力。P529在NCI-60细胞系组中显示出有效的抗增殖活性，生长抑制50（GI 50）<35 μM。此外，P529显着增强辐射对前列腺癌细胞（PC-3）的抗增殖作用。P529靶向的信号通路分析显示放射治疗后p-Akt、VEGF、MMP-2、MMP-9和Id-1水平降低。Bcl-2/Bax比值降低。用20 mg kg−1 P529或6戈伊辐射剂量治疗PC-3荷瘤小鼠，肿瘤大小分别减少了42.9%和53%。两种治疗的组合导致77.4%的肿瘤缩小。肿瘤生长减少是由于增殖减少和凋亡增加（通过PCNA和caspase-3免疫染色评估）。我们的研究结果显示了P529单独和作为放射增敏剂的抗肿瘤功效，并表明该化合物可用于未来治疗人类前列腺癌。
Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) <35 μM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg−1 P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.
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染料木黄酮抑制辐射诱导的NF-kappab在促进凋亡和G2/M细胞周期停滞的前列腺癌细胞中的激活。
影响因子：
3.8
作者：
Raffoul, Julian J.;Wang, Yu;Kucuk, Omer;Forman, Jeffrey D.;Sarkar, Fazlul H.;Hillman, Gilda G.
通讯作者：
Hillman, Gilda G.
影响因子：
3
作者：
Ma, Rundi;Song, Gang;You, Wenbing;Yu, Lijian;Su, Weiming;Liao, Mingneng;Zhang, Yongping;Huang, Laizhen;Zhang, Xiaoyu;Yu, Tingxi
通讯作者：
Yu, Tingxi
影响因子：
2.2
作者：
Gupta, VK;Jaskowiak, NT;Weichselbaum, RR
通讯作者：
Weichselbaum, RR
影响因子：
11.2
作者：
Casarez, Eli V.;Dunlap-Brown, Marya E.;Amorino, George P.
通讯作者：
Amorino, George P.
影响因子：
5.1
作者：
Dai, Jingqiu;Liu, Yang;Nagle, Dale G.
通讯作者：
Nagle, Dale G.