Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice
Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice
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DOI：
10.1158/0008-5472.can-06-3941
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
--
作者：
Khan, Naghma;Afaq, Farrukh;Mukhtar, Hasan
为了开发新的基于机制的肺癌预防方法，我们研究了口服人类可达到的剂量的石榴果提取物(PFE)对两种小鼠肺癌方案的生长、进展、血管生成和信号通路的影响。用苯并(A)芘[B(A)P]和亚硝基三氯乙基脲(NTCU)诱发小鼠肺肿瘤，A/J小鼠饮水中给予PFE。分别于B(A)P给药后第84天、140天和NTCU治疗后240天测定肺肿瘤产额。与只接受致癌物治疗的小鼠相比，接受PFE治疗并暴露于B(A)P和NTCU的小鼠的肺部肿瘤多样性在统计学上显着降低。与B(A)P组相比，B(A)P+PFE组84天和140天的肿瘤缩小率分别为53.9%和61.6%。240d时，NTCU+PFE组较NTCU组肿瘤缩小率为65.9%。免疫印迹分析和免疫组织化学方法检测对细胞存活途径、细胞增殖和血管生成的影响。PFE处理导致抑制(A)核因子-kappaB和ikappaBα激酶的激活，(B)ikappa Bα的降解和磷酸化，(C)丝裂原激活的蛋白激酶(细胞外信号调节激酶1/2、c-jun氨基末端激酶1/2和p38)的磷酸化，(D)磷脂酰肌醇3-激酶(p85和p110)，(E)Akt在Thr处的磷酸化(308)。(F)哺乳动物雷帕霉素信号靶标的激活，(G)c-met的磷酸化，以及(H)细胞增殖(Ki-67和增殖细胞核抗原)和血管生成(诱导型一氧化氮合酶CD31和血管内皮生长因子)的标记物。因此，我们的数据表明，PFE显著抑制了A/J小鼠的肺癌形成，作为一种人类肺癌的化学预防药物值得研究。
To develop novel mechanism-based preventive approaches for lung cancer, we examined the effect of oral consumption of a human achievable dose of pomegranate fruit extract (PFE) on growth, progression, angiogenesis, and signaling pathways in two mouse lung tumor protocols. Benzo(a)pyrene [B(a)P] and iNI-nitroso-tris-chloroethylurea (NTCU) were used to induce lung tumors, and PFE was given in drinking water to A/J mice. Lung tumor yield was examined on the 84th day and 140 days after B(a)P dosing and 240 days after NTCU treatment. Mice treated with PFE and exposed to B(a)P and NTCU had statistically significant lower lung tumor multiplicities than mice treated with carcinogens only. Tumor reduction was 53.9% and 61.6% in the B(a)P + PFE group at 84 and 140 days, respectively, compared with the B(a)P group. The NTCU + PFE group had 65.9% tumor reduction compared with the NTCU group at 240 days. Immunoblot analysis and immunohistochemistry were used to determine effect on cell survival pathways and markers of cellular proliferation and angiogenesis. PFE treatment caused inhibition of (a) activation of nuclear factor-kappa B and I kappa B alpha kinase, (b) degradation and phosphorylation of I kappa B alpha, (c) phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, and p38), (d) phosphatidylinositol 3-kinase (p85 and p110), (e) phosphorylation of Akt at Thr(308). (f) activation of mammalian target of rapamycin signaling, (g) phosphorylation of c-met, and (h) markers of cell proliferation (Ki-67 and proliferating cell nuclear antigen) and angiogenesis (inducible nitric oxide synthase, CD31, and vascular endothelial growth factor) in lungs of B(a)P- and NTCU-treated mice. Thus, our data show that PFE significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer.