Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity
Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity
复制标题
DOI：
10.1074/jbc.m411429200
复制
发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Kumar, AP
中科院分区：
文献类型：
--
作者：
Ghosh, R;Nadiminty, N;Kumar, AP
转移性恶性黑色素瘤是一种极具侵袭性的癌症，目前尚无可行的治疗方法。测试4-烯丙基-2-甲氧基苯酚（丁香酚）抑制黑素瘤细胞增殖的能力。丁香酚而不是其异构体异丁香酚（2-甲氧基-4-丙烯基苯酚）被发现是黑色素瘤细胞增殖的有效抑制剂。在一项B16异种移植研究中，丁香酚治疗产生了显著的肿瘤生长延迟（p = 0.0057），肿瘤大小减少了近40%，达到终点的中位时间增加了19%。更重要的是，对照组中50%的动物死于转移性生长，而治疗组中没有动物显示出任何侵袭或转移的迹象。通过测量体重确定丁香酚耐受性良好。丁香酚在人恶性黑色素瘤细胞系WM 1205 Lu中的抗增殖作用的机制的检查表明，它将细胞阻滞在细胞周期的S期。流式细胞仪结合生化分析表明，丁香酚诱导细胞凋亡。cDNA阵列分析表明，丁香酚引起的E2 F家族的转录因子的失调。瞬时转染实验和电泳迁移率变动实验表明，丁香酚抑制E2 F1的转录活性。E2 F1的过表达恢复了培养物中约75%的增殖能力。这些结果表明，E2 F1的失调可能是丁香酚介导的黑色素瘤生长抑制在体外和体内的一个关键因素。由于E2 F转录因子为黑色素瘤细胞的持续增殖提供了生长动力，这些结果表明丁香酚可以被开发为用于黑色素瘤治疗的E2 F靶向剂。
Metastatic malignant melanoma is an extremely aggressive cancer, with no currently viable therapy. 4-Allyl-2-methoxyphenol (eugenol) was tested for its ability to inhibit proliferation of melanoma cells. Eugenol but not its isomer, isoeugenol (2-methoxy-4-propenylphenol), was found to be a potent inhibitor of melanoma cell proliferation. In a B16 xenograft study, eugenol treatment produced a significant tumor growth delay (p = 0.0057), an almost 40% decrease in tumor size, and a 19% increase in the median time to end point. More significantly, 50% of the animals in the control group died from metastatic growth, whereas none in the treatment group showed any signs of invasion or metastasis. Eugenol was well tolerated as determined by measurement of bodyweights. Examination of the mechanism of the antiproliferative action of eugenol in the human malignant melanoma cell line, WM1205Lu, showed that it arrests cells in the S phase of the cell cycle. Flow cytometry coupled with biochemical analyses demonstrated that eugenol induced apoptosis. cDNA array analysis showed that eugenol caused deregulation of the E2F family of transcription factors. Transient transfection assays and electrophoretic mobility shift assays showed that eugenol inhibits the transcriptional activity of E2F1. Overexpression of E2F1 restored about 75% of proliferation ability in cultures. These results indicate that deregulation of E2F1 may be a key factor in eugenol-mediated melanoma growth inhibition both in vitro and in vivo. Since the E2F transcription factors provide growth impetus for the continuous proliferation of melanoma cells, these results suggest that eugenol could be developed as an E2F-targeted agent for melanoma treatment.