Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells
Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Due to its heterogeneity, the abundance of altered signaling pathways within the same tumoral mass, its low immunogenicity, and the presence of the blood–brain barrier, standard therapies based on surgical resection, radio...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1506206/full |
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| author | Claudio Casali Ludovica Gaiaschi Enrico Pelloni Federica Gola Margherita Cavallo Gloria Milanesi Mauro Ravera Marco Biggiogera Fabrizio De Luca Maria Grazia Bottone |
| author_facet | Claudio Casali Ludovica Gaiaschi Enrico Pelloni Federica Gola Margherita Cavallo Gloria Milanesi Mauro Ravera Marco Biggiogera Fabrizio De Luca Maria Grazia Bottone |
| author_sort | Claudio Casali |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Due to its heterogeneity, the abundance of altered signaling pathways within the same tumoral mass, its low immunogenicity, and the presence of the blood–brain barrier, standard therapies based on surgical resection, radiotherapy, and chemotherapy result in ineffective tumor removal. For these reasons, the development of new drugs is mandatory to ameliorate patients’ life expectancy and quality of life. Cathepsins are lysosomal proteases involved in several physiological and pathological processes, and they play key roles in modulating cell death and pharmacological resistance. In particular, cathepsin B is a crucial regulatory protein in different types of cell death, and its overexpression contributes to GBM angiogenesis and tumor progression. Octahedral platinum(IV) (Pt(IV))-based prodrugs have already demonstrated improved anticancer efficacy compared to routinely used cisplatin. This work aims to investigate the effects of two such prodrugs—Pt(IV)Ac-POA ((OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV)) and DB178 ((OC-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV))—on two different glioblastoma cell lines, U251 and T98G, with particular attention to their effects on cathepsin B. The immunocytochemical and biochemical results obtained on the two cell lines highlight the maintenance of basal levels of cathepsin B while efficiently activating programmed cell death mechanisms, as investigated by optical and electronic microscopy. These findings may serve as a valid starting point for further approaches that incorporate cathepsins’ inhibitors to improve therapeutic efficacy and possibly reveal novel pharmacological targets. |
| format | Article |
| id | doaj-art-529f8d3ff3b84df5b40af32f961527b7 |
| institution | OA Journals |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-529f8d3ff3b84df5b40af32f961527b72025-08-20T02:02:26ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-06-011310.3389/fcell.2025.15062061506206Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cellsClaudio Casali0Ludovica Gaiaschi1Enrico Pelloni2Federica Gola3Margherita Cavallo4Gloria Milanesi5Mauro Ravera6Marco Biggiogera7Fabrizio De Luca8Maria Grazia Bottone9Laboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyDepartment of Sciences and Technological Innovation (DiSIT), University of Piemonte Orientale “A. Avogadro”, Alessandria, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyGlioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Due to its heterogeneity, the abundance of altered signaling pathways within the same tumoral mass, its low immunogenicity, and the presence of the blood–brain barrier, standard therapies based on surgical resection, radiotherapy, and chemotherapy result in ineffective tumor removal. For these reasons, the development of new drugs is mandatory to ameliorate patients’ life expectancy and quality of life. Cathepsins are lysosomal proteases involved in several physiological and pathological processes, and they play key roles in modulating cell death and pharmacological resistance. In particular, cathepsin B is a crucial regulatory protein in different types of cell death, and its overexpression contributes to GBM angiogenesis and tumor progression. Octahedral platinum(IV) (Pt(IV))-based prodrugs have already demonstrated improved anticancer efficacy compared to routinely used cisplatin. This work aims to investigate the effects of two such prodrugs—Pt(IV)Ac-POA ((OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV)) and DB178 ((OC-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV))—on two different glioblastoma cell lines, U251 and T98G, with particular attention to their effects on cathepsin B. The immunocytochemical and biochemical results obtained on the two cell lines highlight the maintenance of basal levels of cathepsin B while efficiently activating programmed cell death mechanisms, as investigated by optical and electronic microscopy. These findings may serve as a valid starting point for further approaches that incorporate cathepsins’ inhibitors to improve therapeutic efficacy and possibly reveal novel pharmacological targets.https://www.frontiersin.org/articles/10.3389/fcell.2025.1506206/fullglioblastomacathepsin Bdrug resistanceplatinum(IV)apoptosismitophagy |
| spellingShingle | Claudio Casali Ludovica Gaiaschi Enrico Pelloni Federica Gola Margherita Cavallo Gloria Milanesi Mauro Ravera Marco Biggiogera Fabrizio De Luca Maria Grazia Bottone Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells Frontiers in Cell and Developmental Biology glioblastoma cathepsin B drug resistance platinum(IV) apoptosis mitophagy |
| title | Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells |
| title_full | Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells |
| title_fullStr | Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells |
| title_full_unstemmed | Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells |
| title_short | Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells |
| title_sort | platinum iv anticancer therapies and cathepsin b innovative strategies for overcoming resistance in glioblastoma cells |
| topic | glioblastoma cathepsin B drug resistance platinum(IV) apoptosis mitophagy |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1506206/full |
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