Abstract
Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O′-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.
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01 March 2021
A Correction to this paper has been published: https://doi.org/10.1007/s10571-020-00896-1
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Acknowledgements
We thank Dr. Giuliano Mazzini (IGM-CNR, Pavia) for his excellent assistance in the Flow cytometric analysis.
Funding
This research was supported by the University of Pavia: Fondi Ricerca Giovani (FRG 2018). This research was also supported by Italian Ministry of Education, University and Research (MIUR): Dipartimenti di Eccellenza Program (2018–2022)—Dept. of Biology and Biotechnology “L. Spallanzani”, University of Pavia. Pawan Faris was gratefully supported by the Italian Ministry of Foreign Affairs and International Cooperation (MAECI).
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All authors had full access to all experimental data and assume responsibility for the integrity and accuracy of data and analysis. VA: execution of experiments, analysis and interpretation of data, and writing the manuscript; PF: execution of experiments and analysis and interpretation of data; BF: preparation and execution of experiments and acquisition and analysis of data; SS: acquisition and analysis of data in electron microscopy; DL: qRT-PCR of the Ca2+ toolkit; BM: acquisition and analysis of data in electron microscopy; DeP SA: synthesis of PTacac; FFP: synthesis of PTacac; RE: analysis of data and critical revision of the manuscript; FM: Study concept, design preparation, and execution of experiments, acquisition and analysis of data, and critical revision of the manuscript; BMG: Study concept and design, analysis of data, and critical revision and finalizing the manuscript.
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The original version of this article was revised: The typo in author name Francesco Paolo Fanizzi was corrected.
Valentina Astesana and Pawan Faris share co-first authorship.
Francesco Moccia and Maria Grazia Bottone are co-last authors.
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10571_2020_873_MOESM1_ESM.tif
Supplementary file1 (TIF 1010 kb)—Supplementary Figure 1. ADP-induced intracellular Ca2+ release is mediated by InsP3Rs. Panel A. ADP-induced intracellular Ca2+ release was prevented by depleting the ER Ca2+ reservoir with CPA (10 M, 30 min), which inhibits SERCA activity thereby causing ER Ca2+ efflux through leakage channels, and by blocking InsP3Rs with 2-APB (50 M, 30 min). ADP was administered at 100 M, whereas extracellular Ca2+ was removed from the bath 100 sec before agonist application in order to exclusively monitor endogenous Ca2+ mobilization. Panel B. mean ± SE of the percentage of T98G cells responding to ADP in the absence and presence of CPA and 2-APB. Panel C. mean ± SE of the amplitude of ADP-induced endogenous Ca2+ release in the absence and presence of CPA and 2-APB.
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Astesana, V., Faris, P., Ferrari, B. et al. [Pt(O,O'-acac)(γ-acac)(DMS)]: Alternative Strategies to Overcome Cisplatin-Induced Side Effects and Resistance in T98G Glioma Cells. Cell Mol Neurobiol 41, 563–587 (2021). https://doi.org/10.1007/s10571-020-00873-8
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DOI: https://doi.org/10.1007/s10571-020-00873-8