Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells
Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells
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DOI：
10.1016/j.jsbmb.2008.11.002
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发表时间：
2009-01-01
影响因子：
4.1
通讯作者：
Kumar, Addanki P.
中科院分区：
文献类型：
--
作者：
Ghosh, Rita;Ganapathy, Manonmani;Kumar, Addanki P.
激素难治性前列腺癌(PCa)治疗缺乏有效的治疗方案，迫切需要开发单独作用或联合作用的新化合物。2-甲氧基雌二醇(2-ME2)是一种内源性雌激素代谢产物，已被报道在包括前列腺癌在内的多种肿瘤模型中作为抗增殖剂。最近在激素难治性前列腺癌(HRPC)患者中进行的临床试验得出结论：2-ME2是安全和耐受性良好的。然而，这项研究发现2-ME2的生物利用度是一个限制因素。在这里，我们报告了2-ME2和丁香酚(4-烯丙基-2-甲氧基苯酚)的组合作为一种增强前列腺癌细胞抗癌活性的方法的能力。联合应用2-ME2和丁香酚(I)抑制前列腺癌细胞的生长并诱导细胞凋亡；(Ii)联合指数(CI)分析显示，联合指数(CI)为0.4，表明有很强的协同作用；(Iii)G(2)/M期细胞数量增加4.5倍(p=0.01)；(Iv)抗凋亡蛋白Bcl2的表达显著减少，促凋亡蛋白Bax的表达增强。联合用药不影响高表达或缺失Bcl2的PC-3细胞的凋亡，但与线粒体膜电位丧失有关。由于2-ME2在HRPC患者的II期试验中耐受性良好，而丁香酚是以香料的形式被人类消耗的，2-ME2与丁香酚的结合可能提供一种新的临床相关治疗方案。如果2-ME2或丁香酚是为人类使用而开发的，则将这些药物组合在一起可能会通过降低2-ME2或丁香酚的单独浓度来缓解这两种药物的不良影响。爱思唯尔有限公司出版。
Lack of effective treatment options for the management of hormone refractory prostate cancer (PCA) reinforce the great need to develop novel compounds that act singly or in combination. 2-Methoxyestradiol (2-ME2) is an endogenous estrogenic metabolite that has been reported to work as an antiproliferative agent in various tumor models including prostate. Recently conducted clinical trial in hormone refractory prostate cancer (HRPC) patients concluded that 2-ME2 was safe and well tolerated. However this study identified bioavailability of 2-ME2 as a limiting factor. Here we report the ability of a combination of 2-ME2 and eugenol (4-allyl-2-methoxyphenol) as an approach for enhancing anticancerous activities in prostate cancer cells. Combining 2-ME2 with eugenol (i) inhibited growth of prostate cancer cells and induced apoptosis at lower concentrations than either single agent alone; (ii) analysis of the data using combination index (CI) showed CI values of 0.4 indicating strong synergistic interaction; (iii) increased population of cells G(2)/M phase by 4.5-fold (p=0.01); (iv) significantly reduced expression of antiapoptotic protein Bcl-2 and enhanced expression of proapoptotic protein Bax. Combination induced apoptosis was not affected in PC-3 cells that over-express or lack Bcl-2 but was associated with loss of mitochondrial membrane potential. Since 2-ME2 was well tolerated in phase II trail in patients with HRPC; and eugenol is consumed by humans in the form of spices, the combination of 2-ME2 with eugenol may offer a new clinically relevant treatment regimen. Combining these agents may allow ameliorating any adverse effects of either 2-ME2 or eugenol alone by reducing their individual concentrations should these two agents be developed for human use. Published by Elsevier Ltd.