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Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo.

Abstract
Estrogen receptor negative (ER(-)) breast cancer is aggressive, responds poorly to current treatments and has a poor prognosis. The NF-κB signaling pathway is implicated in ER(-) tumorigenesis. Aspirin (ASA) is chemopreventive against ER(+) but not for ER(-) breast cancers. Nitric oxide-releasing aspirin (NO-ASA) is a safer ASA where ASA is linked to an NO-releasing moiety through a spacer. In vitro, we investigated anti-proliferation effects of NO-ASA (para- and meta-isomers) against ER(-) breast cancer cells MDA-MB-231 and SK-BR-23, effects on NF-κB signaling, and reactive oxygen species by standard techniques. In vivo, effects of NO-ASA were evaluated in a mouse xenograft model using MDA-MB-231 cells. p-NO-ASA inhibited the growth of MDA-MB-231 and SK-BR-3 cells at 24 h, the respective IC50s were 13 ± 2 and 17 ± 2 μM; ASA had an IC50 of >3000 μM in both cell lines. The IC50s for m-NO-ASA in MDA-MB-231 and SK-BR-3 were 173 ± 15 and 185 ± 12 μM, respectively, therefore, implying p-NO-ASA as a stronger inhibitor of growth p-NO-ASA reduced cell growth by inhibiting proliferation, inducing apoptosis and causing G0/G1 cell cycle block. Activation of NF-κB was inhibited by both isomers as demonstrated by decreases in NF-κB-DNA binding and luciferase activity at 24 h, However, m-NO-ASA produced transient effects at 3 h such as increased NF-κB-DNA-binding, increased levels of nuclear p50, even though both isomers inhibited IκB degradation. Increase in nuclear p50 by m-NO-ASA was associated with translocation of p50 in to the nucleus as observed by immunoflouresence at 3 h. NO-ASA induced reactive oxygen species (ROS) as evidenced by overall increases in both H2DCFDA (2',7'-dichlorodihydrofluorescein) and DHE (dihydroethidium)-derived fluorescence. Inhibition of ROS by N-acetyl-cysteine reversed the m-NO-ASA-mediated translocation of p50 in to the nucleus. In xenografts, p-NO-ASA inhibited tumor growth by inhibiting proliferation (PCNA and tumor volume), inducing apoptosis (TUNEL positive cells) and reducing NF-κB expression. Both isomers inhibit cancer cells, inhibit NF-κB pathway and induce ROS, and have potential as anticancer compounds.
AuthorsNiharika Nath, Mitali Chattopadhyay, Deborah B Rodes, Anna Nazarenko, Ravinder Kodela, Khosrow Kashfi
JournalMolecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 7 Pg. 12481-99 (Jul 09 2015) ISSN: 1420-3049 [Electronic] Switzerland
PMID26184135 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • NF-kappa B
  • Proliferating Cell Nuclear Antigen
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Luciferases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • nitroaspirin
  • Aspirin
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Aspirin (analogs & derivatives, pharmacology)
  • Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Inhibitory Concentration 50
  • Injections, Subcutaneous
  • Luciferases (genetics, metabolism)
  • Mice
  • Mice, Nude
  • NF-kappa B (antagonists & inhibitors, genetics, metabolism)
  • Proliferating Cell Nuclear Antigen (genetics, metabolism)
  • Reactive Oxygen Species (agonists, metabolism)
  • Receptor, ErbB-2 (deficiency, genetics)
  • Receptors, Estrogen (deficiency, genetics)
  • Signal Transduction
  • Xenograft Model Antitumor Assays

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