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Title: NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

Abstract

Highlights: Black-Right-Pointing-Pointer NOSH-aspirin is the first dual acting NO and H{sub 2}S releasing hybrid. Black-Right-Pointing-Pointer Its IC{sub 50} for cell growth inhibition is in the low nano-molar range. Black-Right-Pointing-Pointer Structure-activity studies show that the sum of the parts does not equal the whole. Black-Right-Pointing-Pointer NOSH-aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H{sub 2}S) can increase mucosal defense mechanisms has led to the development of NO- and H{sub 2}S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H{sub 2}S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC{sub 50}s of 45.5 {+-} 2.5, 19.7 {+-} 3.3, and 7.7 {+-} 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G{sub 0}/G{sub 1} cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold moremore » potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation.« less

Authors:
;  [1];  [2];  [1]
  1. Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States)
  2. Department of Physiology, Indiana University School of Medicine, South Bend, IN 46617 (United States)
Publication Date:
OSTI Identifier:
22207754
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 419; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLSALICYLIC ACID; APOPTOSIS; CELL CYCLE; CELL PROLIFERATION; HYBRIDIZATION; HYDROGEN SULFIDES; IN VITRO; INFLAMMATION; INHIBITION; LARGE INTESTINE; MICE; NEOPLASMS; NITRIC OXIDE

Citation Formats

Chattopadhyay, Mitali, Kodela, Ravinder, Olson, Kenneth R., and Kashfi, Khosrow. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.02.051.
Chattopadhyay, Mitali, Kodela, Ravinder, Olson, Kenneth R., & Kashfi, Khosrow. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model. United States. https://doi.org/10.1016/J.BBRC.2012.02.051
Chattopadhyay, Mitali, Kodela, Ravinder, Olson, Kenneth R., and Kashfi, Khosrow. 2012. "NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model". United States. https://doi.org/10.1016/J.BBRC.2012.02.051.
@article{osti_22207754,
title = {NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model},
author = {Chattopadhyay, Mitali and Kodela, Ravinder and Olson, Kenneth R. and Kashfi, Khosrow},
abstractNote = {Highlights: Black-Right-Pointing-Pointer NOSH-aspirin is the first dual acting NO and H{sub 2}S releasing hybrid. Black-Right-Pointing-Pointer Its IC{sub 50} for cell growth inhibition is in the low nano-molar range. Black-Right-Pointing-Pointer Structure-activity studies show that the sum of the parts does not equal the whole. Black-Right-Pointing-Pointer NOSH-aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H{sub 2}S) can increase mucosal defense mechanisms has led to the development of NO- and H{sub 2}S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H{sub 2}S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC{sub 50}s of 45.5 {+-} 2.5, 19.7 {+-} 3.3, and 7.7 {+-} 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G{sub 0}/G{sub 1} cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation.},
doi = {10.1016/J.BBRC.2012.02.051},
url = {https://www.osti.gov/biblio/22207754}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 419,
place = {United States},
year = {Fri Mar 16 00:00:00 EDT 2012},
month = {Fri Mar 16 00:00:00 EDT 2012}
}