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

Antonia Martin-Martin,Alfredo Molina-Berríos,Matías Muñoz-Uribe,Jorge Pérez-Laines,Freddy López-Contreras,Andrés Rivera-Dictter,Rodrigo López-Muñoz

doi:10.3390/molecules24101924

Antonia Martin-Martin, Alfredo Molina-Berríos + Show 5 more

Open Access

https://doi.org/10.3390/molecules24101924

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Abstract

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 (-meta and -para 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 PGE2 levels. NCX4040 released more NO• and significantly decreased PGE2 synthesis relative to NCX4016; however, NO• scavenger treatment reversed the antiproliferative effects of NCX4016, but not those of NCX4040. By contrast, misoprostol (a PGE2 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 PGE2 inhibition is important in the mode of action of NO-aspirins.

Highlights

Lung cancer is a global threat and had the highest estimated incidence and mortality rate of all cancers in 2018 [1]
We evaluated NO release in H1299 cells exposed to aspirin, NCX4016, and NCX4040
Comparisons between NO-aspirin isomers have been performed in HT-29 colon cancer cells, in which NCX4040 and NCX4060 are approximately 100 and 200 times more potent, Comparisons between NO-aspirin isomers have been performed in HT-29 colon cancer cells, in which NCX4040 and NCX4060 are approximately 100 and 200 times more potent, respectively, than

Summary

Introduction

Lung cancer is a global threat and had the highest estimated incidence and mortality rate of all cancers in 2018 [1]. As most newly diagnosed patients with non-small-cell lung cancer (NSCLC). Are at an advanced stage of the disease, the goals of treatment are to improve survival and reduce disease-related events. Current chemotherapy for this malignancy involves the use of cytotoxic drugs, alone or in combination, including platinum derivatives (cisplatin or carboplatin) [2] and antimetabolites (i.e., pemetrexed) [3]. All the drugs used are associated with a variety of adverse effects, and no chemotherapy strategy is proven to increase survival over 10 months for patients with advanced stage disease [5].

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