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Updated: May 25, 2025
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Published on: October 2, 2015
Exploring the Anticancer Potential of NO-Donor Oxadiazole Assemblies Against Malignant Pleural Mesothelioma
Irina A Stebletsova1,2, Alexander A Larin1, Egor M Matnurov3
1N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia.
Abstract:
Background: Nitric oxide (NO) has been linked to the pathogenesis of asbestos-related pleural diseases, including an extremely aggressive cancer called malignant pleural mesothelioma (MPM). Given that MPM cells are characterized by a higher expression of NO synthases and elevated NO production relative to normal cells, the use of NO-donor compounds could potentially saturate the cancerous cells with NO, triggering their death. Methods: We developed a novel class of NO prodrugs by merging two NO-releasing components, 1,2,5-oxadiazole 2-oxides (furoxans) and 1,2,4-oxadiazoles, and studied their NO-releasing characteristics in a time-dependent manner using the Griess assay. The cytotoxicity against two human MPM cell lines and non-cancerous lung fibroblasts was evaluated using a colorimetric MTT assay. Results: All compounds exhibited excellent NO-donating properties, surpassing the capacity of two reference NO donor compounds, 3-carbamoyl-4-(hydroxymethyl)furoxan (CAS-1609) and 4-ethoxy-3-phenylsulphonylfuroxan (CHF-2363), by at least 1.5-3 times. All oxadiazole hybrids demonstrated high cytotoxicity against MPM cell lines in a low micromolar range, comparable or higher than the cytotoxicity of the standard-of-care drug cisplatin. Conclusions: Notably, the novel compounds displayed a markedly greater selectivity towards cancerous cells than cisplatin when compared with non-cancerous lung fibroblasts, aligning with the intended design.
Insights
Novel nitric oxide (NO) prodrugs effectively target malignant pleural mesothelioma (MPM) cells. These compounds show potent NO release and selective cancer cell death, offering a promising therapeutic strategy for asbestos-related lung diseases.
Area of Science:
- Oncology
- Medicinal Chemistry
- Toxicology
Background:
- Nitric oxide (NO) plays a role in asbestos-related pleural diseases, including malignant pleural mesothelioma (MPM).
- MPM cells exhibit higher nitric oxide synthase expression and NO production compared to normal cells.
- Targeting elevated NO in cancer cells with NO-donor compounds offers a potential therapeutic strategy.
Purpose of the Study:
- To develop and evaluate a novel class of NO prodrugs for MPM treatment.
- To assess the NO-releasing capacity and cytotoxicity of these compounds.
- To determine the selectivity of the novel prodrugs against cancerous versus non-cancerous cells.
Main Methods:
- Synthesis of novel NO prodrugs by combining furoxan and oxadiazole moieties.
- Quantification of NO release over time using the Griess assay.
- Evaluation of cytotoxicity against human MPM cell lines and lung fibroblasts via MTT assay.
Main Results:
- All synthesized compounds demonstrated significant NO-donating properties, exceeding reference compounds (CAS-1609, CHF-2363) by 1.5-3 times.
- Oxadiazole hybrids exhibited potent cytotoxicity against MPM cell lines in the low micromolar range.
- The novel compounds showed comparable or superior cytotoxicity to cisplatin against MPM cells.
Conclusions:
- The novel NO prodrugs possess excellent NO-releasing capabilities.
- These compounds demonstrate high efficacy and selectivity against malignant pleural mesothelioma cells.
- The developed prodrugs represent a promising, targeted therapeutic approach for MPM, with improved cancer cell selectivity over cisplatin.
