Nitro-aspirin inhibits MCF-7 breast cancer cell growth: effects on COX-2 expression and Wnt/beta-catenin/TCF-4 signaling.
There is current evidence implicating the Wnt/beta-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57+/-4, 193+/-10 and >5000microM, and for transcriptional inhibition they were 12+/-1.8, 75+/-6.5 and >5000microM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular beta-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.
Nath
Niharika
N
Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, United States. nnath@nyit.edu
Vassell
Rashida
R
Chattopadhyay
Mitali
M
Kogan
Marsel
M
Kashfi
Khosrow
K
D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D004790:Enzyme Induction; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D015398:Signal Transduction / Q000187:drug effects; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
D016588:Anticarcinogenic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C102148:nitroaspirin; D001241:Aspirin