Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo
Abstract
Preclinical studies have shown that nitric oxide (NO)–donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting. [Mol Cancer Ther 2008;7(3):510–20]
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Sodium nitrite therapy may be an effective anti-tumor therapy through NO mediated radiosensitization or tumoricidal properties.
“As discussed above, sodium nitrite therapy may actually be an effective anti-tumor therapy through NO mediated radiosenitization or tumoricidal properties [278, 279].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [279]
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Self-citationDottorato internazionale in Scienze Oncologiche XXVI Ciclo
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BindingDB Entry 50016841: NO-HDAC dual inhibitors.
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BindingDB (2023) · UC San Diego · doi:10.7270/q2xp791q
- Authors
- Maksimovic-Ivanic, D., Mijatovic, S., Harhaji, L., Miljkovic, D., Dabideen, D., Fan Cheng, K., Mangano, K., Malaponte, G., Al-Abed, Y., Libra, M., Garotta, G., Nicoletti, F., & Stosic-Grujicic, S.
- Affiliations
- 1Department of Immunology, Institute for Biological Research “Sinisa Stankovic,” Belgrade University, Belgrade, Serbia;
- Northwell Health (US)
- 2Feinsten Institute for Medical Research, Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Manhasset, New York;
- University of Catania (IT)
- 4Ganial Immunotherapeutics, Inc., Wilmington, Delaware
- Venue
- Molecular Cancer Therapeutics
- Published
- 2008-03-01
- Volume
- 7
- Issue
- 3
- Pages
- 510-520
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2124413854
- Cited by
- 74
- References
- 41
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 9 · 2014: 2 · 2013: 3 · 2012: 10
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Digital Repository of Archived Publications (University of Belgrade, Institute for Biological Research Sinisa Stankovic) (submittedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- nitric oxide donors, isoxazole derivatives, anticancer activity, apoptosis, autophagic cell death, reactive oxygen species, N-acetylcysteine, mitogen-activated protein kinase, cisplatin resistance, B16 melanoma, tumor cell viability, drug tolerability
- MeSH terms
- Acetates, Animals, Antineoplastic Agents, Humans, Mice, Inbred C57BL, Oxazoles, Nitric Oxide Donors, Cell Line, Tumor, Mice
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