Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-κB pathways and inhibits skin tumorigenesis in CD-1 mice
Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-κB pathways and inhibits skin tumorigenesis in CD-1 mice
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DOI：
10.1002/ijc.20587
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发表时间：
2005-01-20
影响因子：
6.4
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
--
作者：
Afaq, F;Saleem, M;Mukhtar, H
化学预防作为一种有效的癌症控制方式已经成熟；然而，对癌症化学预防药物库中新型药物的探索仍在继续。我们认为，能够在致癌过程中的多个关键途径进行干预的药物将比其他单一靶点药物具有更大优势。石榴果实提取物（PFE）源自石榴树，具有很强的抗氧化和抗炎特性。用丙酮提取石榴果实，并基于基质辅助激光解吸/电离飞行时间质谱进行分析，发现其中含有花青素、鞣花单宁和可水解单宁。我们评估了PFE是否具有抗肿瘤促进作用。我们首先确定了局部应用PFE对CD - I小鼠针对12 - O - 十四酰基佛波醇 - 13 - 乙酸酯（TPA）诱导的皮肤肿瘤促进的常规标志物和其他新型标志物的影响。我们发现，在小鼠皮肤上应用TPA（3.2纳摩尔/只）之前30分钟局部应用PFE（2毫克/只），以时间依赖的方式对TPA介导的皮肤水肿和增生、表皮鸟氨酸脱羧酶（ODC）活性以及ODC和环氧合酶 - 2的蛋白质表达的增加有显著抑制作用。我们还发现局部应用PFE导致抑制TPA诱导的ERK1/2、p38和JNK1/2的磷酸化，以及NF - κB和IKKα的激活以及IκBα的磷酸化和降解。接下来我们评估了皮肤应用PFE对7,12 - 二甲基苯并（a）蒽引发的CD - 1小鼠中TPA诱导的皮肤肿瘤促进的影响。与未接受PFE的动物相比，用PFE预处理的动物在以每组肿瘤总数、患肿瘤小鼠的百分比以及每只动物的肿瘤数量来评估时，肿瘤发生率显著降低，肿瘤总体负荷也更低。在TPA处理组中，100%的小鼠在试验16周时发生肿瘤，而在PFE处理组中，此时只有30%的小鼠出现肿瘤。在应用TPA之前皮肤应用PFE还导致潜伏期从9周显著延迟到14周，并且当从肿瘤发生率和肿瘤多发性方面考虑肿瘤数据时提供了保护。我们的研究结果提供了明确的证据，表明PFE在CD - 1小鼠中具有抗皮肤肿瘤促进作用。因为PFE能够抑制TPA诱导的肿瘤促进的常规以及新型生物标志物，它可能在多种肿瘤模型中具有化学预防活性。因此，有必要进行深入研究以确定PFE中能够提供抗肿瘤促进作用的活性成分。
Chemoprevention has come of age as an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable of intervening at more than one critical pathway in the carcinogenesis process will have greater advantage over other single-target agents. Pomegranate fruit extract (PFE) derive from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. Pomegranate fruit was extracted with acetone and analyzed based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and found to contain anthocyanins, ellagitannins and hydrolyzable tannins. We evaluated whether PFE possesses antitumor-promoting effects. We first determined the effect of topical application of PFE to CD-I mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of PFE (2 mg/niouse) 30 min prior to TPA (3.2 nmole/mouse) application on mouse skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in skin edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and protein expression of ODC and cyclooxygeriase-2. We also found that topical application of PFE resulted in,inhibition of TPA-induced phosphorylation of ERK1/2, p38 and JNK1/2, as well as activation of NF-kappaB and IKKalpha and phosphorylation and degradation of IkappaBalpha. We next assessed the effect of skin application of PFE on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated CD-1 mouse. The animals pretreated with PFE showed substantially reduced tumor incidence and lower tumor body burden when assessed as total number of tumors per group, percent of mice with tumors and number of tumors per animal as compared to animals that did not receive PFE. In TPA-treated group, 100% (if the mice developed tumors at 16 weeks on test, whereas at this time in PFE-treated group, only 30% mice exhibited tumors. Skin application of PFE prior to TPA application also resulted in a significant delay in latency period from 9 to 14 weeks and afforded protection when tumor data were considered in terms of tumor incidence and tumor multiplicity. The results of our study provide clear evidence that PFE possesses antiskin-tumor-promoting effects in CD-1 mouse. Because PFE is capable of inhibiting conventional as well as novel biomarkers of TPA-induced tumor promotion, it may possess chemopreventive activity in a wide range of tumor models. Thus, an in-depth study to define active agent(s) in PFE capable of affording antitumor-promoting effect is warranted.