title: Amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in breast cancer MCF-7 cells than is the parent drug.
abstract: A novel amidine analogue of chlorambucil-N-(2-(4-(4-bis(2-chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2-furancarboxamide hydrochloride (AB(1)) and the parent drug were compared for their effects on collagen and DNA biosynthesis in breast cancer MCF-7 cells. IC(50) values for chlorambucil and AB(1) for collagen biosynthesis were found to be about 33 and 13 microM, respectively. The greater potency of AB(1) to suppress collagen synthesis was found to be accompanied by a stronger compared with chlorambucil inhibition of prolidase activity and expression. The phenomenon was related to inhibition of beta(1)-integrin and IGF-I receptor-mediated signaling caused by this compound. The expression of beta(1)-integrin receptor, as well as Src, son of sevenless protein (SOS) and phosphorylated mitogen activated protein (MAP) kinases (MAPK), extracellular-signal-regulated kinase 1 (ERK(1)) and kinase 2 (ERK(2)) but not focal adhesion kinase pp125(FAK) (FAK), Shc, and Grb-2 was significantly decreased in cells incubated for 24 h with 10 microM AB(1) compared to the control, whereas in the same conditions chlorambucil did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. Furthermore, AB(1) induced a stronger down-regulation of the expression of IGF-I receptor and evoked a higher antiproliferative effect. During 12 and 24 h of incubation AB(1) decreased DNA biosynthesis by about 33 % and 51 % of the control, whereas chlorambucil decreased it by about 19 % and 35 %, respectively. These data suggest that the amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in MCF-7 cells than is the parent drug.
authors.affiliation: Department of Medicinal Chemistry, Medical Academy of Białystok, ul. Kilinskiego 1, 15-230 Białystok, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Sienkiewicz
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bielawski
authors.forename: Anna
authors.initials: A
authors.lastname: Bielawska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Pałka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015153:Blotting, Western; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D055765:Shc Signaling Adaptor Proteins; D020664:Son of Sevenless Proteins / Q000096:biosynthesis; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D019012:Integrin beta1; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C501107:chlorambucil-N-(2-(4-(4-bis(2-chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2-furancarboxamide hydrochloride; D002699:Chlorambucil; D003094:Collagen; D004247:DNA; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases