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 (AB1) and the parent drug were compared for their effects on collagen and DNA biosynthesis in breast cancer MCF-7 cells. IC50 values for chlorambucil and AB1 for collagen biosynthesis were found to be about 33 and 13 μM, respectively. The greater potency of AB1 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 β1-integrin and IGF-I receptor-mediated signaling caused by this compound. The expression of β1-integrin receptor, as well as Src, son of sevenless protein (SOS) and phosphorylated mitogen activated protein (MAP) kinases (MAPK), extracellular-signal-regulated kinase 1 (ERK1) and kinase 2 (ERK2) but not focal adhesion kinase pp125FAK (FAK), Shc, and Grb-2 was significantly decreased in cells incubated for 24 h with 10 μM AB1 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, AB1 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 AB1 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.