厚朴酚对 UVB 诱导的小鼠皮肤癌发展的影响及其可能的作用机制。

Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action.

机构信息

Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA.

出版信息

BMC Cancer. 2011 Oct 20;11:456. doi: 10.1186/1471-2407-11-456.

BACKGROUND

Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development.

METHODS

UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle.

RESULTS

Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells.

CONCLUSIONS

Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.

背景

厚朴酚是从厚朴树皮和种子中分离得到的一种植物木脂素，已被证明对化学诱导的皮肤癌发展具有化学预防作用。本研究的目的是研究厚朴酚对 SKH-1 小鼠 UVB 诱导皮肤肿瘤发展的抗癌作用，该模型与人类相关，并确定参与皮肤肿瘤发展的细胞凋亡和细胞周期阻滞的可能作用。

方法

采用 UVB 诱导 SKH-1 小鼠皮肤癌发生模型，观察厚朴酚对皮肤癌发生的预防作用。采用 Western blot 和流式细胞术分析研究厚朴酚对细胞凋亡和细胞周期的影响。

结果

与对照组相比，厚朴酚预处理组（30、60μg）在接受 UVB 处理（30mJ/cm2，每周 5 次）前可使肿瘤多发性降低 27-55%。厚朴酚预处理增加了 caspase-8 和多聚（-ADP-核糖）聚合酶（PARP）的切割，增加了细胞周期抑制剂 p21 的表达，并降低了 SKH-1 小鼠皮肤样本中参与细胞周期 G2/M 期的蛋白质的表达。厚朴酚处理 A431 细胞可浓度依赖性地降低细胞活力和细胞增殖。厚朴酚在 12 小时诱导 A431 细胞 G2/M 期细胞周期阻滞，细胞周期蛋白如 cyclin B1、cyclin A、CDK4、Cdc2 的表达减少，同时 cyclin 依赖性激酶抑制剂 Cip/p21 的表达增加。厚朴酚在体内和体外诱导细胞凋亡，caspase-8 和 PARP 的切割增加。磷酸信号转导子和转录激活子 3（Tyr705）、B-Raf、p-MEK 和 p-AKT 的磷酸化水平降低，而 ERK 的磷酸化水平则被厚朴酚诱导。