Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Inc., 1800 N. Capital Ave., Indianapolis, IN 46202, USA.
Bioorg Med Chem. 2010 Mar 1;18(5):1866-74. doi: 10.1016/j.bmc.2010.01.045. Epub 2010 Jan 25.
The present study describes the characterization and evaluation of novel anticancer conjugates, 2,6-diisopropylphenol-docosahexaenoate (PP-DHA), and its analogues including 2,4-diisopropylphenol-docosahexaenoate (DIPP-DHA), 2-isopropylphenol-docosahexaenoate (IPP-DHA), 2-cyclohexanephenol-docosahexaenoate (CHP-DHA) and phenol-docosahexaenoate (P-DHA) on breast cancer cell lines. Representative breast cancer cell lines, based on estrogen alpha receptor (ER) and oncogene Her-2 expression, were used and include MDA-MB-231 (ER-negative, Her-2-negative), MCF-7 (ER-positive, Her-2-negative) AU565 (ER-negative, Her-2-positive) and MDA-MB-361 (ER-positive, Her-2-positive). The PP-DHA conjugate significantly inhibited cell growth and induced cell loss in the breast cancer cell lines similarly; however, this conjugate was not effective against normal mammary epithelial cells. The effect of various conjugates were in PP-DHA>IPP-DHA>DIPP-DHA>CHP-DHA>>P-DHA order. PP-DHA and IPP-DHA conjugates were stable in human and mouse serum. Furthermore, the non-hydrolyzable amide-linked conjugate analogues affected breast cancer cells in a manner similar to that of the ester-linked conjugates. This suggests that ester-linked PP-DHA and IPP-DHA conjugates were stable during treatment to breast cancer cells due to structural hindrance. PP-DHA did not affect PPARalpha or PPARgamma activities but its anticancer effects appear to be mediated in part though the inhibition of histone deacetylase (HDAC) activity. Further experiments are needed to confirm their molecular target and to test the effectiveness of these compounds in an in vivo model for their anticancer properties. In conclusion, these results suggest that the novel PP-DHA and IPP-DHA conjugates and their amide derivatives may be useful for the treatment of breast cancer.
本研究描述了新型抗癌偶联物 2,6-二异丙基苯酚二十二碳六烯酸酯（PP-DHA）及其类似物，包括 2,4-二异丙基苯酚二十二碳六烯酸酯（DIPP-DHA）、2-异丙基苯酚二十二碳六烯酸酯（IPP-DHA）、2-环己基苯酚二十二碳六烯酸酯（CHP-DHA）和苯酚二十二碳六烯酸酯（P-DHA），对乳腺癌细胞系的特征和评估。基于雌激素 alpha 受体（ER）和癌基因 Her-2 表达，使用了代表性的乳腺癌细胞系，包括 MDA-MB-231（ER 阴性，Her-2 阴性）、MCF-7（ER 阳性，Her-2 阴性）、AU565（ER 阴性，Her-2 阳性）和 MDA-MB-361（ER 阳性，Her-2 阳性）。PP-DHA 偶联物可显著抑制乳腺癌细胞的生长并诱导细胞死亡，但对正常乳腺上皮细胞无效。各种偶联物的效果按 PP-DHA>IPP-DHA>DIPP-DHA>CHP-DHA>>P-DHA 的顺序排列。PP-DHA 和 IPP-DHA 偶联物在人血清和鼠血清中稳定。此外，非水解酰胺键连接的类似物以与酯键连接的偶联物相似的方式影响乳腺癌细胞。这表明酯键连接的 PP-DHA 和 IPP-DHA 偶联物在治疗乳腺癌细胞时由于结构阻碍而稳定。PP-DHA 不影响 PPARalpha 或 PPARgamma 活性，但它的抗癌作用似乎部分通过抑制组蛋白去乙酰化酶（HDAC）活性来介导。需要进一步的实验来确认它们的分子靶标，并测试这些化合物在体内模型中治疗癌症的有效性。总之，这些结果表明，新型的 PP-DHA 和 IPP-DHA 偶联物及其酰胺衍生物可能对治疗乳腺癌有用。
