The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells
Neuroblastoma (NB) is a solid tumor occurring in infancy and childhood. Its high-risk form has currently a survival rate <50%, despite aggressive treatments. This worrying scenario is worsened by drug-induced secondary tumorigenesis and the emergency of drug resistance, calling for the urgent dev...
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2024-09-01
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| author | Silvana Alfei Paolo Giannoni Maria Grazia Signorello Carola Torazza Guendalina Zuccari Constantinos M. Athanassopoulos Cinzia Domenicotti Barbara Marengo |
| author_facet | Silvana Alfei Paolo Giannoni Maria Grazia Signorello Carola Torazza Guendalina Zuccari Constantinos M. Athanassopoulos Cinzia Domenicotti Barbara Marengo |
| author_sort | Silvana Alfei |
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| description | Neuroblastoma (NB) is a solid tumor occurring in infancy and childhood. Its high-risk form has currently a survival rate <50%, despite aggressive treatments. This worrying scenario is worsened by drug-induced secondary tumorigenesis and the emergency of drug resistance, calling for the urgent development of new extra-genomic treatments. Triphenyl phosphonium salts (TPPs) are mitochondria-targeting compounds that exert anticancer effects, impair mitochondria functions, and damage DNA at the same time. Despite several biochemical applications, TPP-based bola-amphiphiles self-assembling nanoparticles (NPs) in water have never been tested as antitumor agents. Here, with the aim of developing new antitumor devices to also counteract resistant forms of HR-NB, the anticancer effects of a TPP-based bola-amphiphile molecule have been investigated in vitro for the first time. To this end, we considered the previously synthesized and characterized sterically hindered quaternary phosphonium salt (BPPB). It embodies both the characteristics of mitochondria-targeting compounds and those of bola-amphiphiles. The anticancer effects of BPPB were assessed against HTLA-230 human stage-IV NB cells and their counterpart, which is resistant to etoposide (ETO), doxorubicin (DOX), and many other therapeutics (HTLA-ER). Very low IC<sub>50</sub> values of 0.2 µM on HTLA-230 and 1.1 µM on HTLA-ER (538-fold lower than that of ETO) were already determined after 24 h of treatment. The very low cell viability observed after 24 h did not significantly differ from that observed for the longest exposure timing. The putative future inclusion of BPPB in a chemotherapeutic cocktail for HR-NB was assessed by investigating in vitro its cytotoxic effects against mammalian cell lines. These included monkey kidney cells (Cos-7, IC<sub>50</sub> = 4.9 µM), human hepatic cells (HepG2, IC<sub>50</sub> = 9.6 µM), a lung-derived fibroblast cell line (MRC-5, IC<sub>50</sub> = 2.8 µM), and red blood cells (RBCs, IC<sub>50</sub> = 14.9 µM). Appreciable to very high selectivity indexes (SIs) have been determined after 24 h treatments (SIs = 2.5–74.6), which provided evidence that both NB cell populations were already fully exterminated. These in vitro results pave the way for future investigations of BPPB on animal models and upon confirmation for the possible development of BPPB as a novel therapeutic to treat MDR HR-NB cells. |
| format | Article |
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| institution | OA Journals |
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| spelling | doaj-art-1d8c868fbc224e908e858793ab59cf692025-08-20T01:55:44ZengMDPI AGNanomaterials2079-49912024-09-011418150510.3390/nano14181505The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma CellsSilvana Alfei0Paolo Giannoni1Maria Grazia Signorello2Carola Torazza3Guendalina Zuccari4Constantinos M. Athanassopoulos5Cinzia Domenicotti6Barbara Marengo7Department of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, ItalyBiochemistry Laboratory, Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genova, ItalyDepartment of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, ItalyDepartment of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, ItalyDepartment of Chemistry, Campus Rio Achaias, University of Patras, 26504 Rio, GreeceDepartment of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, ItalyNeuroblastoma (NB) is a solid tumor occurring in infancy and childhood. Its high-risk form has currently a survival rate <50%, despite aggressive treatments. This worrying scenario is worsened by drug-induced secondary tumorigenesis and the emergency of drug resistance, calling for the urgent development of new extra-genomic treatments. Triphenyl phosphonium salts (TPPs) are mitochondria-targeting compounds that exert anticancer effects, impair mitochondria functions, and damage DNA at the same time. Despite several biochemical applications, TPP-based bola-amphiphiles self-assembling nanoparticles (NPs) in water have never been tested as antitumor agents. Here, with the aim of developing new antitumor devices to also counteract resistant forms of HR-NB, the anticancer effects of a TPP-based bola-amphiphile molecule have been investigated in vitro for the first time. To this end, we considered the previously synthesized and characterized sterically hindered quaternary phosphonium salt (BPPB). It embodies both the characteristics of mitochondria-targeting compounds and those of bola-amphiphiles. The anticancer effects of BPPB were assessed against HTLA-230 human stage-IV NB cells and their counterpart, which is resistant to etoposide (ETO), doxorubicin (DOX), and many other therapeutics (HTLA-ER). Very low IC<sub>50</sub> values of 0.2 µM on HTLA-230 and 1.1 µM on HTLA-ER (538-fold lower than that of ETO) were already determined after 24 h of treatment. The very low cell viability observed after 24 h did not significantly differ from that observed for the longest exposure timing. The putative future inclusion of BPPB in a chemotherapeutic cocktail for HR-NB was assessed by investigating in vitro its cytotoxic effects against mammalian cell lines. These included monkey kidney cells (Cos-7, IC<sub>50</sub> = 4.9 µM), human hepatic cells (HepG2, IC<sub>50</sub> = 9.6 µM), a lung-derived fibroblast cell line (MRC-5, IC<sub>50</sub> = 2.8 µM), and red blood cells (RBCs, IC<sub>50</sub> = 14.9 µM). Appreciable to very high selectivity indexes (SIs) have been determined after 24 h treatments (SIs = 2.5–74.6), which provided evidence that both NB cell populations were already fully exterminated. These in vitro results pave the way for future investigations of BPPB on animal models and upon confirmation for the possible development of BPPB as a novel therapeutic to treat MDR HR-NB cells.https://www.mdpi.com/2079-4991/14/18/1505high-risk neuroblastoma (HR-NB)HTLA-230 NB and HTLA-ER cellstriphenyl phosphonium groupsmitochondrial targetsbola-amphiphilesnanosized vesicles |
| spellingShingle | Silvana Alfei Paolo Giannoni Maria Grazia Signorello Carola Torazza Guendalina Zuccari Constantinos M. Athanassopoulos Cinzia Domenicotti Barbara Marengo The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells Nanomaterials high-risk neuroblastoma (HR-NB) HTLA-230 NB and HTLA-ER cells triphenyl phosphonium groups mitochondrial targets bola-amphiphiles nanosized vesicles |
| title | The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells |
| title_full | The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells |
| title_fullStr | The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells |
| title_full_unstemmed | The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells |
| title_short | The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells |
| title_sort | remarkable and selective in vitro cytotoxicity of synthesized bola amphiphilic nanovesicles on etoposide sensitive and resistant neuroblastoma cells |
| topic | high-risk neuroblastoma (HR-NB) HTLA-230 NB and HTLA-ER cells triphenyl phosphonium groups mitochondrial targets bola-amphiphiles nanosized vesicles |
| url | https://www.mdpi.com/2079-4991/14/18/1505 |
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