Studies on the inhibition of tumor cell growth and microtubule assembly by 3-hydroxy-4-[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2-dione, an intensively coloured Maillard reaction product.
Very recently, 3-hydroxy-4-[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2-dione (1) has been successfully identified as an intensively coloured Maillard product formed from glucose and L-proline upon thermal food processing. Using a biomimetic synthetic strategy, reference material of compound 1 was prepared and purified, and then used to study its effect on the growth of human tumor cells. Compound 1 was found to potently inhibit the growth of human tumor cells in vitro. Using a reporter gene assay we could show that in growth inhibitory concentrations compound 1 effectively inhibits the phosphorylation of the transcription factor Elk-1. In addition, 1 was found to affect the microtubule skeleton. The human mammary carcinoma cell line MCF-7 exhibits a decrease of the microtubule organisation when treated for 24 h with 1 (> or =20 microM). At concentrations of 30 microM and above a loss of microtubule integrity is observed after 1 h incubation. In vitro studies demonstrated that the polymerisation and, to a minor extent, also the depolymerisation of tubulin, isolated and purified from bovine brain, is inhibited in a dose-dependent manner at concentrations of 30 microM and above. This is the first time that a non-enzymatically formed browning compound of known structure was reported to effectively inhibit tumor cell growth and microtubule assembly.
Marko
D
D
Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserslautern Erwin-Schroedinger-Str. 52, 67663, Kaiserslautern, Germany. marko@rhrk.uni-kl.de
Kemény
M
M
Bernady
E
E
Habermeyer
M
M
Weyand
U
U
Meiers
S
S
Frank
O
O
Hofmann
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001923:Brain Chemistry; D001943:Breast Neoplasms / Q000473:pathology; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D003517:Cyclopentanes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D015416:Maillard Reaction; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011108:Polymers / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
C444300:3-hydroxy-4-(-(2-furyl)methylidene)methyl-3-cyclopentene-1,2-dione; D000970:Antineoplastic Agents; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D005663:Furans; D011108:Polymers; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014404:Tubulin; D050807:ets-Domain Protein Elk-1