The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells.
The antiproliferative activity of the aspirin derivative [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS) and its analogue hexacarbonyl[μ-(2-ethylphenyl)methanol]dicobalt (Co-EPM) was investigated on malignant pleural mesothelioma (MPM) cell lines, having an epithelioid or a sarcomatoid phenotype. In sarcomatoid cell lines Co-ASS was more potent than Co-EPM and the prototypal metallo-drug cisplatin, and induced cell death through the intrinsic apoptotic pathway, associated with a strong NF-κB inhibition. In contrast, both Co-ASS and Co-EPM showed only a modest cytostatic activity against epithelioid MPM cells. Co-EPM induced an increase of senescent cells, while Co-ASS did not; the different outcomes were traced back to the organic (aspirin-like) portion of the molecule. Both Co-EPM and Co-ASS significantly reduced reactive oxygen/nitrogen species (ROS/RNS), and in turn nitrites, suggesting that the hexacarbonyldicobalt moiety may deliver CO within the cell, acting as a CO-releasing molecule (CO-RM). In perspective, Co-ASS would be better considered as a CO-NSAID agent (a CO-releasing molecule retaining the NSAID properties similar to NO- and H2S-NSAIDs) than as an antitumor drug candidate.
Dipartimento di Scienze e Innovazione Tecnologica (DiSIT), Sezione Ambiente-Vita, Università del Piemonte Orientale "A. Avogadro", Viale T. Michel 11, 15121 Alessandria, Italy. domenico.osella@unipmn.it.
Ilaria
I
Zanellato
Ilaria
I
Bonarrigo
Mauro
M
Ravera
Elisabetta
E
Gabano
Ronald
R
Gust
Domenico
D
Osella
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D003035:Cobalt; D002248:Carbon Monoxide; D001241:Aspirin