alpha-Tocopheryl succinate as a scaffold to develop potent inhibitors of breast cancer cell adhesion.
This study is aimed at the pharmacological exploitation of alpha-tocopheryl succinate (1) to develop potent antiadhesion agents. Considering the structural cooperativity between the phytyl chain and the carboxylic terminus in determining the antiadhesion activity, our structural optimization led to compound 5 ([2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-acetic acid), which exhibited an-order-of-magnitude higher potency than 1 in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins (IC(50), 0.6 microM versus 10 microM). Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis.
Wang
Dasheng
D
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 336 Parks Hall, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
Chuang
Hsiao-Ching
HC
Weng
Shu-Chuan
SC
Huang
Po-Hsien
PH
Hsieh
Hao-Yu
HY
Kulp
Samuel K
SK
Chen
Ching-Shih
CS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055808:Drug Discovery; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009362:Neoplasm Metastasis; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D024502:alpha-Tocopherol / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D051416:Focal Adhesion Protein-Tyrosine Kinases; D024502:alpha-Tocopherol