Reconsidering the Role of Cyclooxygenase Inhibition in the Chemotherapeutic Value of NO-Releasing Aspirins for Lung Cancer

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 10; p. 1924
• Main Authors: Martin-Martin, Antonia, Rivera-Dictter, Andrés, Muñoz-Uribe, Matías, López-Contreras, Freddy, Pérez-Laines, Jorge, Molina-Berríos, Alfredo, López-Muñoz, Rodrigo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.05.2019; MDPI
• Subjects: Acids; Antiproliferatives; Antitumor activity; Aspirin; Cancer therapies; Cell adhesion & migration; Cell viability; Chemotherapy; Colorectal cancer; cyclooxygenase; Cytotoxicity; Epidermal growth factor; erlotinib; Growth factors; Isomers; Kinases; Lung cancer; Misoprostol; Mode of action; Mutation; NCX4016; NCX4040; Nitric oxide; Non-small cell lung carcinoma; non-small-cell lung cancer; Nonsteroidal anti-inflammatory drugs; Ovarian cancer; prostaglandin; Prostaglandin E2; Prostaglandin endoperoxide synthase; Prostate cancer; Synergistic effect; Targeted cancer therapy; NCX4040; nitric oxide; prostaglandin; erlotinib; cyclooxygenase; NCX4016; non-small-cell lung cancer
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24101924

Nitric oxide-releasing aspirins (NO-aspirins) are aspirin derivatives that are safer than the parent drug in the gastrointestinal context and have shown superior cytotoxic effects in several cancer models. Despite the rationale for their design, the influence of nitric oxide (NO ) on the effects of NO-aspirins has been queried. Moreover, different isomers exhibit varying antitumor activity, apparently related to their ability to release NO . Here, we investigated the effects and mode of action of NO-aspirins in non-small-cell lung cancer (NSCLC) cells, comparing two isomers, NCX4016 and NCX4040 ( and isomers, respectively). NCX4040 was more potent in decreasing NSCLC cell viability and migration and exhibited significant synergistic effects in combination with erlotinib (an epidermal growth factor receptor inhibitor) in erlotinib-resistant cells. We also studied the relationship among the effects of NO-aspirins, NO release, and PGE levels. NCX4040 released more NO and significantly decreased PGE synthesis relative to NCX4016; however, NO scavenger treatment reversed the antiproliferative effects of NCX4016, but not those of NCX4040. By contrast, misoprostol (a PGE receptor agonist) significantly reversed the antiproliferative effect of NCX4040, but not those of NCX4016. Furthermore, misoprostol reversed the antimigratory effects of NCX4040. Overall, these results indicate that PGE inhibition is important in the mode of action of NO-aspirins.