Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in VivoReportar como inadecuado




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1

Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, USA

2

Department of Life Sciences, New York Institute of Technology, New York, NY 10023, USA

3

Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA





*

Authors to whom correspondence should be addressed.



Academic Editor: Derek J. McPhee

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. View Full-Text

Keywords: NSAIDs; NO-NSAIDs; NF-κB; oxidative stress; breast cancer; estrogen receptor NSAIDs; NO-NSAIDs; NF-κB; oxidative stress; breast cancer; estrogen receptor





Autor: Niharika Nath 1,2,* , Mitali Chattopadhyay 1, Deborah B. Rodes 1, Anna Nazarenko 1, Ravinder Kodela 1 and Khosrow Kashfi 1,3,*

Fuente: http://mdpi.com/



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