A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer
Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modifi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.846958/full |
| _version_ | 1818669693978804224 |
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| author | Stefania Zuppone Chiara Assalini Claudia Minici Oronza A. Botrugno Flavio Curnis Massimo Degano Angelo Corti Angelo Corti Francesco Montorsi Francesco Montorsi Andrea Salonia Andrea Salonia Riccardo Vago Riccardo Vago |
| author_facet | Stefania Zuppone Chiara Assalini Claudia Minici Oronza A. Botrugno Flavio Curnis Massimo Degano Angelo Corti Angelo Corti Francesco Montorsi Francesco Montorsi Andrea Salonia Andrea Salonia Riccardo Vago Riccardo Vago |
| author_sort | Stefania Zuppone |
| collection | DOAJ |
| description | Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG peptide (RGD-4C), an αv-integrin ligand, and explored the anti-tumor activity of the resulting protein (called RGD-SAP) in vitro and in vivo, using a model of muscle invasive bladder cancer. We found that the RGD-4C targeting domain enhances the cytotoxic activity of SAP against various tumor cell lines, in a manner dependent on αv-integrin expression levels. In a subcutaneous syngeneic model of bladder cancer, RGD-SAP significantly reduced tumor growth in a dose-dependent manner. Furthermore, systemic administration of RGD-SAP in combination with mitomycin C, a chemotherapeutic drug currently used to treat patients with bladder cancer, increased the survival of mice bearing orthotopic bladder cancer with no evidence of systemic toxicity. Overall, the results suggest that RGD-SAP represents an efficient drug that could be exploited, either alone or in combination with the state-of-the-art therapies, for the treatment of bladder cancer and, potentially, of other solid tumors. |
| first_indexed | 2024-12-17T06:56:17Z |
| format | Article |
| id | doaj.art-e32562cd4c1948f695e2baa6a239f800 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-17T06:56:17Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e32562cd4c1948f695e2baa6a239f8002022-12-21T21:59:25ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-04-011210.3389/fonc.2022.846958846958A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder CancerStefania Zuppone0Chiara Assalini1Claudia Minici2Oronza A. Botrugno3Flavio Curnis4Massimo Degano5Angelo Corti6Angelo Corti7Francesco Montorsi8Francesco Montorsi9Andrea Salonia10Andrea Salonia11Riccardo Vago12Riccardo Vago13Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyUrological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyBiocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, ItalyFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyBiocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, ItalyTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyFaculty of Medicine and Surgery, Università Vita-Salute San Raffaele, Milano, ItalyUrological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyFaculty of Medicine and Surgery, Università Vita-Salute San Raffaele, Milano, ItalyUrological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyFaculty of Medicine and Surgery, Università Vita-Salute San Raffaele, Milano, ItalyUrological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, ItalyFaculty of Medicine and Surgery, Università Vita-Salute San Raffaele, Milano, ItalyAlthough toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG peptide (RGD-4C), an αv-integrin ligand, and explored the anti-tumor activity of the resulting protein (called RGD-SAP) in vitro and in vivo, using a model of muscle invasive bladder cancer. We found that the RGD-4C targeting domain enhances the cytotoxic activity of SAP against various tumor cell lines, in a manner dependent on αv-integrin expression levels. In a subcutaneous syngeneic model of bladder cancer, RGD-SAP significantly reduced tumor growth in a dose-dependent manner. Furthermore, systemic administration of RGD-SAP in combination with mitomycin C, a chemotherapeutic drug currently used to treat patients with bladder cancer, increased the survival of mice bearing orthotopic bladder cancer with no evidence of systemic toxicity. Overall, the results suggest that RGD-SAP represents an efficient drug that could be exploited, either alone or in combination with the state-of-the-art therapies, for the treatment of bladder cancer and, potentially, of other solid tumors.https://www.frontiersin.org/articles/10.3389/fonc.2022.846958/fullsaporinrecombinant proteinbladder cancerRGD peptidetargeted therapyribosome inactivating proteins |
| spellingShingle | Stefania Zuppone Chiara Assalini Claudia Minici Oronza A. Botrugno Flavio Curnis Massimo Degano Angelo Corti Angelo Corti Francesco Montorsi Francesco Montorsi Andrea Salonia Andrea Salonia Riccardo Vago Riccardo Vago A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer Frontiers in Oncology saporin recombinant protein bladder cancer RGD peptide targeted therapy ribosome inactivating proteins |
| title | A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer |
| title_full | A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer |
| title_fullStr | A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer |
| title_full_unstemmed | A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer |
| title_short | A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer |
| title_sort | novel rgd 4c saporin conjugate inhibits tumor growth in mouse models of bladder cancer |
| topic | saporin recombinant protein bladder cancer RGD peptide targeted therapy ribosome inactivating proteins |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.846958/full |
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