nystatin-a1 and Breast-Neoplasms

A series of novel methylene bis-isoxazolo[4,5-b]azepines have been synthesized by reaction of 3,5-dimethyl-4-nitroisoxazole 6 with an appropriate methylene bis-chalcones 7 to obtain various Michael adducts 8a-i, which on treatment with SnCl(2)-MeOH underwent reductive cyclization to afford the title compounds 9a-i. Structure of these compounds were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectral data. The title compounds 9a-i were evaluated for their in vitro antimicrobial and anticancer activities. Compounds 9h and 9i exhibited potent antimicrobial and anticancer activities as that of standard drugs.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azepines; Bacteria; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Drug Design; Female; Humans; Isoxazoles; Kidney; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship

uPAR and MMP-9, which play critical roles in tumor cell invasion, migration and angiogenesis, have been shown to be associated with lipid rafts.. To investigate whether cholesterol could regulate uPAR and MMP-9 in breast carcinoma, we used MβCD (methyl beta cyclodextrin, which extracts cholesterol from lipid rafts) to disrupt lipid rafts and studied its effect on breast cancer cell migration, invasion, angiogenesis and signaling.. Morphological evidence showed the association of uPAR with lipid rafts in breast carcinoma cells. MβCD treatment significantly reduced the colocalization of uPAR and MMP-9 with lipid raft markers and also significantly reduced uPAR and MMP-9 at both the protein and mRNA levels. Spheroid migration and invasion assays showed inhibition of breast carcinoma cell migration and invasion after MβCD treatment. In vitro angiogenesis studies showed a significant decrease in the angiogenic potential of cells pretreated with MβCD. MβCD treatment significantly reduced the levels of MMP-9 and uPAR in raft fractions of MDA-MB-231 and ZR 751 cells. Phosphorylated forms of Src, FAK, Cav, Akt and ERK were significantly inhibited upon MβCD treatment. Increased levels of soluble uPAR were observed upon MβCD treatment. Cholesterol supplementation restored uPAR expression to basal levels in breast carcinoma cell lines. Increased colocalization of uPAR with the lysosomal marker LAMP1 was observed in MβCD-treated cells when compared with untreated cells.. Taken together, our results suggest that cholesterol levels in lipid rafts are critical for the migration, invasion, and angiogenesis of breast carcinoma cells and could be a critical regulatory factor in these cancer cell processes mediated by uPAR and MMP-9.

Topics: beta-Cyclodextrins; Breast Neoplasms; Caveolins; Cell Line, Tumor; Cell Movement; Cholesterol; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Focal Adhesion Kinase 1; Gene Expression Regulation; Humans; Matrix Metalloproteinase 9; Membrane Microdomains; Neoplasm Invasiveness; Neovascularization, Pathologic; Nystatin; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Urokinase Plasminogen Activator; RNA, Messenger; src-Family Kinases; Time Factors