A3 Adenosine and P2X7 Purinergic Receptors as New Targets for an Innovative Pharmacological Therapy of Malignant Pleural Mesothelioma

Our plain-English summary of A3 Adenosine and P2X7 Purinergic Receptors as New Targets for an Innovative Pharmacological Therapy of Malignant Pleural Mesothelioma, by F. Vincenzi, J.C. Rotondo, S. Pasquini, et al (Frontiers in Oncology, 2021).

The study

• Authors: F. Vincenzi, J.C. Rotondo, S. Pasquini, F. Di Virgilio, K. Varani, M. Tognon
• Journal: Frontiers in Oncology
• Published: 2021;11:679285
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Human malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor of the serosal cavities whose 5-year survival rate is 15%. At present, there are no effective therapies for MPM. Although recent findings suggest that A3 adenosine (A3AR) and P2X7 (P2X7R) receptors can be employed as antitumoral pharmacological targets in MPM, their potential role in a combined therapy is currently unknown. The A3AR agonist Cl-IB-MECA and the P2X7 receptor antagonist AZ10606120, as a single compound or in combination, were investigated in vitro for their anti-tumor activities. Assays were carried out in MPM cell lines IST-Mes2 and MPP89 and in primary human normal mesothelial cells (HMCs), as control. Single treatment with Cl-IB-MECA reduced cell proliferation and favored a pro-apoptotic effect in both MPP89 and IST-Mes2 cell lines, whereas AZ10606120 inhibited cell proliferation and induced apoptosis in IST-Mes2, only. The combined treatment with Cl-IB-MECA and AZ10606120 reduced cell proliferation and favored apoptosis in MPP89 and IST-Mes2 cell lines, whereas no synergistic effect was detected. These data cumulatively suggest the absence of a synergistic effect in combined targeting of A3 adenosine and P2X7 receptors of MPM cell lines. This study may stimulate further investigations aimed at determining new combinations of antitumor compounds and more effective therapeutic strategies against MPM.

Copyright © 2021 Vincenzi, Rotondo, Pasquini, Di Virgilio, Varani and Tognon.

In plain English

This Italian laboratory study tested two drugs on cultured cells. It involved no patients and no asbestos. The authors treated two malignant pleural mesothelioma cell lines (IST-Mes2 and MPP89) and normal mesothelial cells for up to 72 hours. Cl-IB-MECA (100 nM) activates the A3 adenosine receptor, and AZ10606120 (300 nM) blocks the P2X7 receptor. The drugs were given alone or together. Cl-IB-MECA reduced proliferation of both tumor lines (by 37% in MPP89 cells at 72 hours). AZ10606120 reduced proliferation of IST-Mes2 cells (33% at 72 hours) but not of MPP89 cells, though it lowered MPP89 viability by 21%. The combination did not reduce proliferation significantly more than a single drug in IST-Mes2 cells, or more than Cl-IB-MECA alone in MPP89 cells. In normal cells, neither drug significantly changed proliferation, and the authors reported viability was not affected. Cl-IB-MECA raised a cell-death marker (caspase 3/7) in both tumor lines, while AZ10606120 raised it only in IST-Mes2. Annexin V staining, cleaved PARP-1 and, in IST-Mes2 cells, cytochrome C release showed no increase. The authors concluded that the combination had no synergistic effect. They suggested the Cl-IB-MECA dose might have been too low.

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) experiment on cultured cell lines; n=3 independent experiments conducted in triplicate
• Who was studied: Two human malignant pleural mesothelioma (MPM) cell lines, IST-Mes2 and MPP89, plus primary human normal mesothelial cells (HMCs) as controls; University of Ferrara, Italy
• Exposure: No asbestos exposure was studied. Cells were treated with the A3 adenosine receptor agonist Cl-IB-MECA (1 nM to 1 µM in dose-finding tests, then 100 nM), with or without the P2X7 receptor antagonist AZ10606120 (300 nM), for 24, 48 and 72 hours. Cisplatin and etoposide were used as positive controls.
• Main results:
  • IST-Mes2 cells had a lower density of A3 adenosine receptors than MPP89 cells (Bmax 118 plus or minus 8 versus 317 plus or minus 25 fmol/mg protein)
  • In IST-Mes2 cells, Cl-IB-MECA reduced proliferation by 22% at 72 hours (p less than 0.05)
  • In IST-Mes2 cells, AZ10606120 reduced proliferation by 30% at 48 hours and by 33% at 72 hours
  • In IST-Mes2 cells, the combination's reduction in proliferation did not differ significantly from the effect of the single compound
  • In MPP89 cells, Cl-IB-MECA reduced proliferation by 22% at 48 hours and by 37% at 72 hours
  • In MPP89 cells, AZ10606120 did not affect proliferation at any time point (p greater than 0.05)
  • In MPP89 cells, the combination's effect on proliferation did not differ significantly from Cl-IB-MECA alone
  • In MPP89 cells, after 72 hours of treatment, AZ10606120 reduced cell viability by 21% (p less than 0.05)
  • In MPP89 cells, the combination reduced viability by 34%, which was not significantly different from Cl-IB-MECA alone (32%)
  • In normal mesothelial cells, neither drug, alone or combined, produced a statistically significant change in proliferation (p greater than 0.05)
  • The authors reported that viability of normal mesothelial cells was not affected by either drug, alone or combined
  • In IST-Mes2 cells at 72 hours, caspase 3/7 activation increased by 31% with Cl-IB-MECA, by 37% with AZ10606120 and by 38% with the combination
  • In MPP89 cells, Cl-IB-MECA increased caspase 3/7 activation by 40% at 48 hours and by 43% at 72 hours, while AZ10606120 had no effect
  • Neither drug, alone or combined, increased Annexin V positive cells in any of the cell types
  • No cleaved PARP-1 was found in IST-Mes2 or MPP89 cells after 72 hours of treatment with either drug or the combination
  • No cytochrome C release was found in IST-Mes2 cells after 72 hours of treatment with either drug or the combination
• The authors' conclusion: The authors concluded that the combined treatment reduced proliferation and favored apoptosis in the MPM cell lines but did not show a synergistic effect
• Limitations the authors state:
  • The lack of synergy might be due to insufficient dosing of Cl-IB-MECA
  • A synergistic effect at Cl-IB-MECA concentrations above 100 nM cannot be excluded

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Apoptosis, Synergistic Effect.

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