The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells

Our plain-English summary of The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells, by I. Zanellato, I. Bonarrigo, M. Ravera, et al (Metallomics, 2013).

The study

• Authors: I. Zanellato, I. Bonarrigo, M. Ravera, E. Gabano, R. Gust, D. Osella
• Journal: Metallomics
• Published: 2013;5(12):1604-13
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This laboratory study tested an experimental cobalt-containing derivative of aspirin, Co-ASS, on cells grown in dishes; no patients or asbestos exposures were studied. The cells came from malignant pleural mesothelioma: BR95 (epithelioid), MG06 (mixed), MM98 (sarcomatoid) and a cisplatin-resistant MM98 sub-line, with normal mesothelial cells as a control. Comparisons were Co-EPM, a similar cobalt compound without the aspirin part, aspirin, and cisplatin. In 72-hour growth tests on MM98 cells, Co-ASS was more potent than cisplatin (half-maximal inhibitory concentration 1.7 versus 3.2 micromolar). In 24-hour tests on MM98 cells, Co-ASS above 10 micromolar triggered programmed cell death, and it inhibited NF-κB most strongly of the compounds tested. It was about 10 times less potent on epithelial-like BR95 and MG06 cells, and in BR95 it only slowed growth. Both cobalt compounds lowered reactive oxygen and nitrogen species in BR95 and MM98 mesothelioma cells. Separately, in stimulated leukemia cells, they cut nitrite by about 25%, which the authors read as a sign of carbon monoxide release. The authors concluded that Co-ASS is better considered a carbon-monoxide-releasing anti-inflammatory agent than an antitumor drug candidate.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture experiment testing drug compounds on human cell lines. No patients and no asbestos exposure were studied.
• Who was studied: Human malignant pleural mesothelioma cell lines from the mesothelioma bio-bank at the City Hospital of Alessandria, Italy. They were established from pleural effusions of previously untreated patients: BR95 (epithelioid), MG06 (mixed, with epithelial predominance) and MM98 (sarcomatoid), plus MM98R, a cisplatin-resistant sub-line of MM98. Also used were normal human mesothelial cells (HMC) from hernia sacs of premature babies as a non-tumor control, colon cancer HCT-116 cells, lung cancer A549 cells, and HL-60 leukemia cells for the nitrite test.
• Exposure: The cobalt-aspirin compound Co-ASS ([2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt), compared with the related cobalt compound Co-EPM (no aspirin part), aspirin (ASA) and cisplatin. Growth tests used 72 hours of continuous treatment, and the apoptosis and NF-κB tests used 24 hours. No asbestos exposure was studied.
• Main results:
  • After 72 hours, in sarcomatoid MM98 cells, the half-maximal inhibitory concentration (IC50) of Co-ASS was 1.7 plus or minus 0.7 µM, versus 3.2 plus or minus 1.0 µM for cisplatin. In the cisplatin-resistant MM98R cells, it was 3.2 plus or minus 0.8 µM for Co-ASS versus 19.4 plus or minus 2.8 µM for cisplatin.
  • In the epithelial-like cell lines, the IC50 of Co-ASS was about 10 times higher, meaning lower activity: 15.1 µM in BR95 and 24.7 µM in MG06.
  • The selectivity index compares the effect on tumor cells with the effect on normal mesothelial cells. For Co-ASS it was 3.6 in MM98, but 0.4 in BR95 and 0.3 in MG06.
  • In the clonogenic (colony-forming) assay, the IC50 of Co-ASS was 0.050 µM in MM98 cells, versus 28.0 µM in BR95 cells. In BR95 the authors interpreted the effect of Co-ASS as cytostatic (growth slowing). MG06 was not tested in this assay.
  • After 24 hours of treatment, Co-ASS activated caspase-3, a marker of programmed cell death (apoptosis), only in MM98 cells, at Co-ASS concentrations above 10 µM. It did not do so in BR95 cells.
  • After 24 hours, in MM98 cells, all treatments decreased NF-κB activity, with the strongest inhibition from Co-ASS. In BR95 cells, NF-κB activity rose significantly only with Co-ASS.
  • Both cobalt compounds significantly reduced reactive oxygen species in both mesothelioma cell types (BR95 and MM98). The authors note that the assay detects both reactive oxygen and reactive nitrogen species.
  • In a separate experiment on stimulated HL-60 leukemia cells, both cobalt compounds reduced nitrite levels by about 25%. The authors interpreted this as carbon-monoxide-releasing activity.
  • After one week of treatment of BR95 cells, Co-ASS produced fewer senescent cells than Co-EPM (less than 10%).
• The authors' conclusion: The authors concluded that Co-ASS would be better considered a CO-NSAID agent (a carbon-monoxide-releasing molecule that keeps aspirin-like anti-inflammatory properties) than an antitumor drug candidate.
• Limitations the authors state:
  • The authors note that some Co-ASS could break down during the 72-hour continuous treatment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Epithelioid, Sarcomatoid, Cisplatin.

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