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首页> 外文期刊>Life sciences >Chemopreventive effect of farnesol on DMBA/TPA-induced skin tumorigenesis: involvement of inflammation, Ras-ERK pathway and apoptosis.
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Chemopreventive effect of farnesol on DMBA/TPA-induced skin tumorigenesis: involvement of inflammation, Ras-ERK pathway and apoptosis.

机译：法尼醇对DMBA / TPA诱导的皮肤肿瘤发生的化学预防作用：涉及炎症，Ras-ERK途径和细胞凋亡。

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AIMS: Naturally-derived farnesol has been reported for its chemopreventive and chemotherapeutic efficacy in various cancers. However, the mechanism of action of farnesol is still to be elucidated. The present study demonstrates the chemopreventive potential of farnesol on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis in Swiss albino mice. MAIN METHODS: Farnesol at three different doses 25, 50 and 100 mg/kg body weight was topically applied to the mouse skin, 30 min prior to TPA (2 microg/200 microl acetone) to evaluate edema, hyperplasia, expression of cyclooxygenase-2 (COX-2), oxidative stress response and hyperproliferation, and expression of Ras, Raf, p-ERK1/2, Bax and Bcl-2 in DMBA/TPA-induced tumors. KEY FINDINGS: Farnesol at both the low doses significantly reduced the TPA-induced skin edema, hyperplasia, expression of COX-2 and oxidative stress response. Interestingly, higher dose of farnesol did not show any significant response. Pretreatment of farnesol significantly decreased TPA-induced ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation in dose-dependent manner. During promotion phase, farnesol with higher dose significantly regressed tumor incidence and tumor burden with an extension of latency period of 4-8 weeks. More importantly, low doses of farnesol significantly inhibited Ras/Raf/ERK1/2 signaling pathway in mouse skin tumors whereas higher dose of farnesol induced the pathway. Moreover, farnesol at all doses altered Bax/Bcl-2 ratio which leads to induction of apoptosis as confirmed by DNA fragmentation. SIGNIFICANCE: These findings revealed that oxidative stress, inflammation, Ras/Raf/ERK1/2 pathway and apoptosis collectively played a crucial role in the chemopreventive activity of farnesol to inhibit the murine skin tumorigenesis.
机译：目的：据报道天然来源的法尼醇在各种癌症中具有化学预防和化学治疗的功效。然而，仍需阐明法尼醇的作用机理。本研究证明了法尼醇对9,10-二甲基苯并（a）蒽（DMBA）引发和12-O-十四烷酰phorbol-13-乙酸酯（TPA）促进的瑞士白化病小鼠皮肤的化学预防潜力。主要方法：在TPA（2 microg / 200 microl丙酮）之前30分钟，将三种不同剂量的法尼醇25、50和100 mg / kg体重局部施用于小鼠皮肤，以评估水肿，增生，环氧合酶2的表达（COX-2），氧化应激反应和过度增殖，以及DMBA / TPA诱导的肿瘤中Ras，Raf，p-ERK1 / 2，Bax和Bcl-2的表达。主要发现：两种低剂量的法尼醇都显着降低了TPA诱导的皮肤水肿，增生，COX-2表达和氧化应激反应。有趣的是，较高剂量的法尼醇没有显示任何明显的反应。法尼醇的预处理以剂量依赖的方式显着降低了TPA诱导的鸟氨酸脱羧酶（ODC）活性和[（3）H]胸苷的掺入。在促进阶段，高剂量的法尼醇可显着降低肿瘤发生率和肿瘤负担，延长潜伏期4-8周。更重要的是，低剂量的法尼醇可显着抑制小鼠皮肤肿瘤中的Ras / Raf / ERK1 / 2信号传导途径，而更高剂量的法尼醇可诱导该途径。而且，法尼醇在所有剂量下都改变了Bax / Bcl-2比率，这导致了DNA片段化的诱导凋亡。意义：这些发现表明，氧化应激，炎症，Ras / Raf / ERK1 / 2途径和细胞凋亡在法呢醇抑制鼠皮肤肿瘤发生的化学预防活性中起着至关重要的作用。

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