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一种新型RGD-4C-皂草素偶联物可抑制膀胱癌小鼠模型中的肿瘤生长。

A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer.

作者信息

Zuppone Stefania, Assalini Chiara, Minici Claudia, Botrugno Oronza A, Curnis Flavio, Degano Massimo, Corti Angelo, Montorsi Francesco, Salonia Andrea, Vago Riccardo

机构信息

Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.

Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.

出版信息

Front Oncol. 2022 Apr 11;12:846958. doi: 10.3389/fonc.2022.846958. eCollection 2022.

DOI:10.3389/fonc.2022.846958
PMID:35480108
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9035931/
Abstract

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) and , 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.

摘要

尽管在癌症治疗中，毒素与化疗药物相比可能具有一些优势，例如强大的细胞毒性活性和降低的耐药风险，但它们在实体瘤治疗中的成功应用仍有待充分证明。在本研究中，我们通过将植物源单链核糖体失活蛋白皂草素（SAP）的N端与αv整合素配体ACDCRGDCFCG肽（RGD-4C）融合，对其结构进行了基因改造，并利用肌肉浸润性膀胱癌模型探索了所得蛋白（称为RGD-SAP）的抗肿瘤活性。我们发现，RGD-4C靶向结构域以依赖于αv整合素表达水平的方式增强了SAP对各种肿瘤细胞系的细胞毒性活性。在膀胱癌皮下同基因模型中，RGD-SAP以剂量依赖的方式显著降低了肿瘤生长。此外，将RGD-SAP与目前用于治疗膀胱癌患者的化疗药物丝裂霉素C联合全身给药，提高了原位膀胱癌荷瘤小鼠的生存率，且无全身毒性迹象。总体而言，结果表明RGD-SAP是一种有效的药物，可单独或与现有最佳疗法联合用于治疗膀胱癌以及潜在地治疗其他实体瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/bffa74cce155/fonc-12-846958-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/95fad3b846e2/fonc-12-846958-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/730743a2dd3b/fonc-12-846958-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/8c9617e54670/fonc-12-846958-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/89a38796c471/fonc-12-846958-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/b1cab8374196/fonc-12-846958-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/d00ba663c7a0/fonc-12-846958-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/adf119e61dd6/fonc-12-846958-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/bffa74cce155/fonc-12-846958-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/95fad3b846e2/fonc-12-846958-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/730743a2dd3b/fonc-12-846958-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/8c9617e54670/fonc-12-846958-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/89a38796c471/fonc-12-846958-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/b1cab8374196/fonc-12-846958-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/d00ba663c7a0/fonc-12-846958-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/adf119e61dd6/fonc-12-846958-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bec/9035931/bffa74cce155/fonc-12-846958-g008.jpg

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