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Open AccessArticle

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

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
Molecules 2015, 20(7), 12481-12499; https://doi.org/10.3390/molecules200712481
Received: 9 April 2015 / Revised: 11 June 2015 / Accepted: 6 July 2015 / Published: 9 July 2015
(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)
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
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MDPI and ACS Style

Nath, N.; Chattopadhyay, M.; Rodes, D.B.; Nazarenko, A.; Kodela, R.; Kashfi, K. Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo. Molecules 2015, 20, 12481-12499. https://doi.org/10.3390/molecules200712481

AMA Style

Nath N, Chattopadhyay M, Rodes DB, Nazarenko A, Kodela R, Kashfi K. Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo. Molecules. 2015; 20(7):12481-12499. https://doi.org/10.3390/molecules200712481

Chicago/Turabian Style

Nath, Niharika; Chattopadhyay, Mitali; Rodes, Deborah B.; Nazarenko, Anna; Kodela, Ravinder; Kashfi, Khosrow. 2015. "Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo" Molecules 20, no. 7: 12481-12499. https://doi.org/10.3390/molecules200712481

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