Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model.
Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model.
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DOI：
10.18632/oncotarget.10733
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Damodaran C
中科院分区：
文献类型：
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作者：
Suman S;Das TP;Moselhy J;Pal D;Kolluru V;Alatassi H;Ankem MK;Damodaran C
我们之前报道过，一种天然化合物醉茄素A（WA）通过抑制AKT同时诱导细胞凋亡来阻止前列腺癌。在目前的研究中，我们使用转基因小鼠前列腺腺癌（TRAMP）模型研究了其对前列腺癌发生的化学预防功效。进行了两组不同的实验。为了确定WA是否延迟肿瘤进展，在癌症发作前、第6周和直到第44周给予WA。为了确定其在前列腺癌发作后的效果，从第12周至第35周给予。在这两种策略中，当与媒介物处理的动物相比时，口服给予WA有效地抑制了肿瘤负荷。在大体病理学检查时，在给药动物中未观察到毒性。Western blot分析和肿瘤切片的免疫组化显示，在TRAMP对照中，AKT和pAKT高表达，而核FOXO 3a和Par-4下调。相反，经处理的小鼠显示AKT信号传导的抑制和FOX 03 a-Par-4诱导的细胞死亡的激活。它们还显示出间充质标志物如β-连环蛋白、波形蛋白和snail的抑制以及E-钙粘蛋白的上调。由于表达的血管生成标志物因子VIII和网织红细胞的下调，WA的抗血管生成的作用。总体而言，我们的研究结果表明，WA可能是一个有前途的抗癌剂，有效地抑制前列腺癌的发生。
We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate.