Characterization of anticancer properties of 2,6-diisopropylphenol-docosahexaenoate and analogues in breast cancer cells.

Abstract

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.

• Authors: Kevin A Harvey, Zhidong Xu, Phillip Whitley, V Jo Davisson, Rafat A Siddiqui
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 5 Pg. 1866-74 (Mar 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20153203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 2,6-diisopropylphenol docosahexaenoate
• Antineoplastic Agents, Hormonal
• Estrogen Receptor alpha
• Docosahexaenoic Acids
• Receptor, ErbB-2
• Histone Deacetylases
• Propofol

Topics

• Animals
• Antineoplastic Agents, Hormonal (chemical synthesis, chemistry, therapeutic use)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Docosahexaenoic Acids (chemical synthesis, chemistry, therapeutic use)
• Estrogen Receptor alpha (metabolism)
• Female
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Mice
• Propofol (chemistry)
• Receptor, ErbB-2 (metabolism)