In Vitro Activity of Monofunctional Pt-II Complex Based on 8-Aminoquinoline against Human Glioblastoma

Our plain-English summary of In Vitro Activity of Monofunctional Pt-II Complex Based on 8-Aminoquinoline against Human Glioblastoma, by V. Coccè, I. Rimoldi, G. Facchetti, et al (Pharmaceutics, 2021).

The study

• Authors: V. Coccè, I. Rimoldi, G. Facchetti, E. Ciusani, G. Alessandri, L. Signorini, F. Sisto, A. Giannì, F. Paino, A. Pessina
• Journal: Pharmaceutics
• Published: 2021;13(12)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

A new cationic Pt(II) complex bearing 8-aminoquinoline as chelating ligand (called Pt-8AQ) was evaluated against two human carcinomas, one mesothelioma, and three glioblastoma cell lines. The in vitro comparison to the clinically approved CisPt showed a minor activity of Pt-8AQ against carcinoma and mesothelioma, whereas a significant activity of Pt-8AQ was observed on the proliferation of the three glioblastoma cell lines (U87-MG IC50 = 3.68 ± 0.69 µM; U373-MG IC50 = 11.53 ± 0.16 µM; U138-MG IC50 = 8.05 ± 0.23 µM) that was higher than that observed with the clinically approved CisPt (U87-MG IC50 = 7.27 + 1.80 µM; U373-MG IC50 = 22.69 ± 0.05 µM; U138-MG IC50 = 32.1 ± 4.44 µM). Cell cycle analysis proved that Pt-8AQ significantly affected the cell cycle pattern by increasing the apoptotic cells represented by the sub G0/G1 region related with a downregulation of p53 and Bcl-2. Moreover, an NMR investigation of Pt-8AQ interaction with 9-EtG, GSH, and Mets7 excluded DNA as the main target, suggesting a novel mechanism of action. Our study demonstrated the high stability of Pt-8AQ after incubation at 37 °C and a significant antineoplastic activity on glioblastomas. These features also make Pt-8AQ a good candidate for developing a new selective advanced cell chemotherapy approach in combination with MSCs.

In plain English

This laboratory study tested a new platinum compound, Pt-8AQ, on human tumor cells grown in culture, comparing it with the approved drug cisplatin (CisPt). It did not study asbestos or people. Six cell lines were used: three glioblastoma (brain tumor) lines, two carcinoma lines (pancreatic adenocarcinoma CFPAC-1 and adenocarcinoma MCF-7) and one biphasic mesothelioma line, MSTO-211H. Cisplatin showed higher activity than Pt-8AQ on the carcinoma and mesothelioma lines. On the glioblastoma lines U87-MG, U373-MG and U138-MG, Pt-8AQ was more active. The concentrations that halved cell growth (IC50) were 3.68, 11.53 and 8.05 µM for Pt-8AQ, against 7.27, 22.69 and 32.1 µM for cisplatin. After 24 hours at 37 °C, Pt-8AQ kept part of its activity on U87-MG cells, while no cisplatin IC50 could be detected. Pt-8AQ led to high proportions of glioblastoma cells that the authors read as apoptotic (dying). The authors concluded that DNA was not the main target of Pt-8AQ and that it showed clear efficacy against glioblastomas regardless of p53 gene status. They described the study as preliminary.

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: Preliminary in vitro laboratory study on cultured human tumor cell lines, with chemical (NMR and mass spectrometry) binding tests
• Who was studied: Six human tumor cell lines: glioblastoma lines U87-MG (wild-type p53), U373-MG and U138-MG (mutant p53); pancreatic adenocarcinoma CFPAC-1; adenocarcinoma MCF-7; and biphasic mesothelioma MSTO-211H. No human subjects.
• Exposure: No asbestos exposure was studied. The cells were treated with two drugs: cisplatin (CisPt) and the new platinum(II) complex Pt-8AQ. The 7-day growth tests used serial dilutions from 0.52 to 64 µM CisPt and from 0.27 to 35.52 µM Pt-8AQ. Other tests used 2.5 to 20 µM or 10 µM.
• Main results:
  • On the carcinoma lines and the mesothelioma line (MSTO-211H), cisplatin showed higher activity than Pt-8AQ. The article does not print the IC50 numbers for these lines in readable text.
  • On the glioblastoma lines, Pt-8AQ IC50 values in the 7-day growth test were: U87-MG 3.68 ± 0.69 µM; U373-MG 11.53 ± 0.16 µM; U138-MG 8.05 ± 0.23 µM. The authors reported the difference from cisplatin as statistically significant (p < 0.01).
  • Cisplatin IC50 values on the glioblastoma lines were: U87-MG 7.27 (printed '+ 1.80') µM; U373-MG 22.69 ± 0.05 µM; U138-MG 32.1 ± 4.44 µM.
  • Stability: after 24 h at 37 °C, the Pt-8AQ IC50 on U87-MG cells rose from 3.68 ± 0.69 µM to 8.39 ± 0.79 µM (a 2.27-fold decrease in activity). No cisplatin IC50 was detectable up to the 70 µM tested.
  • In the 24-h viability test at 20 µM, Pt-8AQ produced 70–80% cytotoxicity on U87-MG and U373-MG and 60% on U138-MG. Cisplatin had a maximal cytotoxic effect of 10–15%.
  • In cell cycle analysis at 10 µM, Pt-8AQ put 80% of U87-MG cells in the sub G0/G1 (apoptotic) region after 96 h, and 100% of U373-MG and U138-MG cells after 48 h. Cisplatin increased the proportion of cells in S phase.
  • After 24 h, both drugs significantly downregulated p53, except Pt-8AQ in U138-MG cells. Both drugs also downregulated the anti-apoptotic gene BCL-2 in all three glioblastoma lines.
  • The authors interpreted the NMR binding study with 9-ethylguanine, a DNA model base, as showing that DNA is not the main target of Pt-8AQ.
• The authors' conclusion: The authors concluded that Pt-8AQ showed clear efficacy against glioblastomas, independently of their p53 gene status, and was stable at 37 °C. They reported they are working on mesenchymal stromal cells (MSCs) loaded with Pt-8AQ for local delivery.
• Limitations the authors state:
  • The data are not sufficient to establish the role of the different p53 mutations in the cell lines.
  • Cell death pathways other than apoptosis could not be excluded; further investigation is needed.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Mesothelioma, Chemotherapy.

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