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.
Highlights
Human malignant pleural mesothelioma (MPM) is a highly aggressive tumor of the serosal cavities with a 5-year survival rate of approximately 15%, whereas MPM patients die approximately one year after diagnosis
Data showed that the highest effect of Cl-IB-MECA on cell proliferation inhibition and apoptosis induction was obtained at 100 nM (Figures 2A–D)
The A3 adenosine receptor (A3AR) agonist Cl-IB-MECA and the P2X7R antagonist AZ10606120 were investigated for their growth inhibition effects in MPM cell lines
Summary
Human malignant pleural mesothelioma (MPM) is a highly aggressive tumor of the serosal cavities with a 5-year survival rate of approximately 15%, whereas MPM patients die approximately one year after diagnosis. MPM is considered a rare tumor, statistical data estimate that onequarter million people could die of this malignancy in Europe in the three decades [1]. MPM exhibits a strong association to asbestos fiber exposure, such as crocidolite, amosite, and chrysotile [3,4,5]. As for other tumors [6,7,8], the genetic background/mutations in different genes is another important risk factor of the MPM onset. Epidemiological data suggest that the genetic background is essential in determining the individual susceptibility to the asbestos-related MPM onset [11]. Only a fraction of subjects carrying a specific genetic background develop this tumor [13], which is estimated to be approximately 1%-10% of ex-exposed asbestos workers [14,15,16], depending on the study being considered [2]
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