Department of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, MN, USA.
Int J Cancer. 2012 Oct 1;131(7):1720-31. doi: 10.1002/ijc.27409. Epub 2012 Feb 18.
Activated Kras gene coupled with activation of Akt and nuclear factor-kappa B (NF-κB) triggers the development of pancreatic intraepithelial neoplasia, the precursor lesion for pancreatic ductal adenocarcinoma (PDAC) in humans. Therefore, intervention at premalignant stage of disease is considered as an ideal strategy to delay the tumor development. Pancreatic malignant tumor cell lines are widely used; however, there are not relevant cell-based models representing premalignant stages of PDAC to test intervention agents. By employing a novel Kras-driven cell-based model representing premalignant and malignant stages of PDAC, we investigated the efficacy of ACTICOA-grade cocoa polyphenol (CP) as a potent chemopreventive agent under in vitro and in vivo conditions. It is noteworthy that several human intervention/clinical trials have successfully established the pharmacological benefits of cocoa-based foods. The liquid chromatography (LC)-mass spectrometry (MS)/MS data confirmed epicatechin as the major polyphenol of CP. Normal, nontumorigenic and tumorigenic pancreatic ductal epithelial (PDE) cells (exhibiting varying Kras activity) were treated with CP and epicatechin. CP and epicatechin treatments induced no effect on normal PDE cells, however, caused a decrease in the (i) proliferation, (ii) guanosine triphosphate (GTP)-bound Ras protein, (iii) Akt phosphorylation and (iv) NF-κB transcriptional activity of premalignant and malignant Kras-activated PDE cells. Further, oral administration of CP (25 mg/kg) inhibited the growth of Kras-PDE cell-originated tumors in a xenograft mouse model. LC-MS/MS analysis of the blood showed epicatechin to be bioavailable to mice after CP consumption. We suggest that (i) Kras-driven cell-based model is an excellent model for testing intervention agents and (ii) CP is a promising chemopreventive agent for inhibiting PDAC development.
激活的 Kras 基因与 Akt 和核因子-κB（NF-κB）的激活共同触发了胰腺上皮内瘤变的发生，这是人类胰腺导管腺癌（PDAC）的癌前病变。因此，在疾病的癌前阶段进行干预被认为是延迟肿瘤发展的理想策略。胰腺恶性肿瘤细胞系被广泛应用；然而，目前还没有相关的基于细胞的模型来代表 PDAC 的癌前阶段，以测试干预剂。通过采用一种新的 Kras 驱动的基于细胞的模型来代表 PDAC 的癌前和恶性阶段，我们研究了 ACTICOA 级可可多酚（CP）作为一种有效的化学预防剂在体外和体内条件下的疗效。值得注意的是，几项人类干预/临床试验已经成功确立了可可食品的药理益处。液相色谱（LC）-质谱（MS）/MS 数据证实表儿茶素是 CP 的主要多酚。正常的、非肿瘤性和肿瘤性胰腺导管上皮（PDE）细胞（表现出不同的 Kras 活性）用 CP 和表儿茶素进行处理。CP 和表儿茶素处理对正常 PDE 细胞没有影响，但导致（i）增殖、（ii）鸟苷三磷酸（GTP）结合 Ras 蛋白、（iii）Akt 磷酸化和（iv）癌前和恶性 Kras 激活的 PDE 细胞的 NF-κB 转录活性降低。此外，CP（25mg/kg）的口服给药抑制了异种移植小鼠模型中 Kras-PDE 细胞起源的肿瘤的生长。CP 消耗后血液中的 LC-MS/MS 分析显示表儿茶素对小鼠具有生物利用度。我们提出（i）Kras 驱动的基于细胞的模型是测试干预剂的极好模型，（ii）CP 是抑制 PDAC 发展的有前途的化学预防剂。
