NDLI: Inhibition of collagen and DNA biosynthesis by a novel amidine analogue of chlorambucil is accompanied by deregulation of ß(1)-integrin and IGF-I receptor signaling in MDA-MB 231 cells.

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Inhibition of collagen and DNA biosynthesis by a novel amidine analogue of chlorambucil is accompanied by deregulation of ß(1)-integrin and IGF-I receptor signaling in MDA-MB 231 cells.

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Inhibition of collagen and DNA biosynthesis by a novel amidine analogue of chlorambucil is accompanied by deregulation of ß(1)-integrin and IGF-I receptor signaling in MDA-MB 231 cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sienkiewicz, Pawel Bielawski, Krzysztof Bielawska, Anna Palka, Jerzy
Description	Country affiliation: Poland Author Affiliation: Sienkiewicz P ( Department of Medicinal Chemistry, Medical Academy of Bialystok, ul. Kilinskiego 1, 15-089 Bialystok, Poland.)
Abstract	A novel amidine analogue of chlorambucil N-(2-(4-(4-bis(2-chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2-furanecarboxamide hydrochloride (AB(1)), and the parent drug were compared for their effects on collagen and DNA synthesis in breast cancer MDA-MB 231 cells. IC(50) values for chlorambucil and its amidine analogue for collagen synthesis were found to be about 44 and 19µM, respectively. Increased ability of AB(1) to suppress the protein synthesis, compared to chlorambucil, was found to be related to an inhibition of prolidase activity and expression. The phenomena were probably a result of disruption of ß(1)-integrin and the insulin-like growth factor-I (IGF-I) receptor mediated signaling caused by this compound. Expression of ß(1)-integrin receptor, as well as focal adhesion kinase pp125(FAK) (FAK), growth-factor receptor-bound protein 2 (GRB2), son of sevenless protein 1 (Sos1) and phosphorylated mitogen activated protein kinases (MAPK), extracellular-signal-regulated kinase 1 (ERK(1)) and kinase 2 (ERK(2)) but not Src and Shc proteins was significantly decreased in cells incubated for 24h with 10µM AB(1), compared to controls. Chlorambucil in the same conditions did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. In addition, AB(1) revealed a higher antiproliferative activity than chlorambucil, accompanied by a stronger down-regulation of IGF-I receptor expression. The results were confirmed by [(3)H]thymidine incorporation assay. Incubation of the cells with 10µM AB(1) for 12 and 24h contributed to a decrease in DNA synthesis by about 33 and 46% of the control values, respectively, while in case of chlorambucil by about 23 and 29%, respectively. These data suggest that the amidine analogue of chlorambucil (AB(1)) disturbs MDA-MB 231 cell metabolism more potently than does the parent drug, chlorambucil. The mechanism of this phenomenon may be due to its stronger suppression of ß(1)-integrin and IGF-I receptor signaling.
File Format	HTM / HTML
ISSN	13826689
Issue Number	1
Journal	Environmental Toxicology and Pharmacology
Volume Number	20
e-ISSN	18727077
Language	English
Publisher	Elsevier
Publisher Date	2005-07-01
Publisher Place	Netherlands
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Environmental Health Discipline Pharmacology
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology Pharmacology

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Inhibition of collagen and DNA biosynthesis by a novel amidine analogue of chlorambucil is accompanied by deregulation of ß(1)-integrin and IGF-I receptor signaling in MDA-MB 231 cells.