NCX 4016, a nitric oxide-releasing aspirin derivative, exhibits a significant antiproliferative effect and alters cell cycle progression in human colon adenocarcinoma cell lines.
Nitric oxide-releasing non-steroidal antiinflammatory drugs (NO-NSAIDs) are safer than NSAIDs due to their ability to reduce gastric toxicity. We assessed the cytotoxic activity of a new aspirin derivative, NCX 4016, after different exposure schedules, in three human colon adenocarcinoma cell lines. All the lines were positive for COX-1 protein and mRNA, as evaluated by Western blot and RT-PCR, respectively, while only one was positive for COX-2. The cytostatic and cytocidal activity was determined by sulforhodamine B assay and evaluated according to Monks' model. Cytostatic activity was observed after a 24-h drug exposure and 50% growth inhibition was reached at concentrations ranging from 165 to 250 micro M in all cell lines, whereas with aspirin the IC50 was never reached, even at the maximum concentration tested (500 micro M), and was independent of COX-1 or COX-2 status. Cytocidal activity was observed only at the highest concentrations and persisted for a long time after drug removal. Flow cytometric analysis showed that the NO-aspirin compound induced a persistent accumulation of cells in G2-M phase in all the cell lines after at least 48 h exposure. Specifically, the block pertained mainly to G2 phase, whereas mitotic index was not affected at all. Our results indicate that NCX 4016 has an in vitro cytostatic activity superior to that of its parental aspirin compound, which makes it a potentially important tumor preventive agent. Furthermore, the cytocidal effect observed at the highest concentrations and the induction of a specific block in G2 phase renders it a promising candidate for drug combination treatments.
Istituto Oncologico Romagnolo, Pierantoni Hospital, Forlì, Italy.
Anna
A
Tesei
Luca
L
Ricotti
Paola
P
Ulivi
Laura
L
Medri
Dino
D
Amadori
Wainer
W
Zoli
D000230:Adenocarcinoma / Q000473:pathology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C102148:nitroaspirin; D001241:Aspirin