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

Mitali Chattopadhyay, Ravinder Kodela, Kenneth Olson, Khosrow Kashfi

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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 2S) can increase mucosal defense mechanisms has led to the development of NO- and H 2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H 2S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC 50s of 45.5±2.5, 19.7±3.3, and 7.7±2.2nM at 24, 48, and 72h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G 0/G 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.

Original languageEnglish
Pages (from-to)523-528
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume419
Issue number3
DOIs
StatePublished - Mar 16 2012

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Hydrogen Sulfide
Cell growth
Heterografts
Colonic Neoplasms
Nitric Oxide
Growth
Anti-Inflammatory Agents
Sheep
Gasotransmitters
Bearings (structural)
Pharmaceutical Preparations
Gastrin-Secreting Cells
Cell proliferation
4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate
In Vitro Techniques
Neoplasms
Cell Cycle
Cells
Cell Proliferation
Apoptosis

Keywords

  • Anti-colon cancer
  • Anti-inflammatory
  • Aspirin
  • Chemoprevention
  • Colon cancer
  • Hydrogen sulfide
  • Nitric oxide
  • NOSH-aspirin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

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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 = "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 2S) can increase mucosal defense mechanisms has led to the development of NO- and H 2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H 2S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC 50s of 45.5±2.5, 19.7±3.3, and 7.7±2.2nM at 24, 48, and 72h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G 0/G 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.",
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T1 - 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

AU - Chattopadhyay, Mitali

AU - Kodela, Ravinder

AU - Olson, Kenneth

AU - Kashfi, Khosrow

PY - 2012/3/16

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N2 - 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 2S) can increase mucosal defense mechanisms has led to the development of NO- and H 2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H 2S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC 50s of 45.5±2.5, 19.7±3.3, and 7.7±2.2nM at 24, 48, and 72h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G 0/G 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.

AB - 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 2S) can increase mucosal defense mechanisms has led to the development of NO- and H 2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H 2S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC 50s of 45.5±2.5, 19.7±3.3, and 7.7±2.2nM at 24, 48, and 72h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G 0/G 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.

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