title: Novel coumarin-3-(N-aryl)carboxamides arrest breast cancer cell growth by inhibiting ErbB-2 and ERK1.
abstract: A series of novel coumarin carboxamides were synthesized, and their tumor cell cytotoxic activity was investigated. These compounds specifically inhibited the growth of cancer cells that have a high level of ErbB-2 expression. Immunoprecipitation analysis of the cell lysates prepared from carboxamide treated cancer cells showed the inhibition of ErbB-2 phosphorylation suggesting the interaction of these compounds with ErbB-2 receptor. The down regulation of the kinase activity was further confirmed by performing in vitro kinase assay with recombinant ErbB-2 incubated with carboxamides. The inhibition of ErbB-2 phosphorylation correlated with down-regulation of ERK1 MAP kinase activation that is involved in proliferative signaling pathway. Furthermore, the cell-killing activity of many of these inhibitors is restricted to tumor cells with no demonstrable cytotoxicity against normal human fibroblasts suggesting that these compounds are tumor-specific.
authors.affiliation: Fels Institute for Cancer Research, Temple University School of Medicine, 3307, North Broad Street, Philadelphia, PA 19140-5101, USA.
authors.forename: Natala Srinivasa
authors.initials: NS
authors.lastname: Reddy
authors.forename: Kiranmai
authors.initials: K
authors.lastname: Gumireddy
authors.forename: Muralidhar R
authors.initials: MR
authors.lastname: Mallireddigari
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Padmavathi
authors.initials: P
authors.lastname: Venkatapuram
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Bell
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000577:Amides; D003374:Coumarins; D048052:Mitogen-Activated Protein Kinase 3; D018719:Erb-b2 Receptor Tyrosine Kinases