NRPa-308, a new neuropilin-1 antagonist, exerts in vitro anti-angiogenic and anti-proliferative effects and in vivo anti-cancer effects in a mouse xenograft model
| Autor: | Rachid Benhida, Wang-Qing Liu, Sylvie Dufour, Yves Lepelletier, Olivier Hermine, Bertrand Leforban, Renaud Grépin, Françoise Raynaud, Luc Demange, Christiane Garbay, Rafika Jarray, Matthieu Montes, Ali Loukaci, Gilles Pagès, Réda Hadj-Slimane, Lucia Borriello |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Angiogenesis Angiogenesis Inhibitors Mice SCID Pharmacology Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mice Inbred NOD In vivo Cell Line Tumor Neoplasms Neuropilin 1 medicine Animals Humans Cytotoxic T cell Viability assay Cells Cultured Cell Proliferation Mice Knockout Molecular Structure Sunitinib Cancer medicine.disease Survival Analysis Xenograft Model Antitumor Assays Neuropilin-1 Tumor Burden Vascular endothelial growth factor 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis medicine.drug |
| Zdroj: | Cancer Letters. 414:88-98 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2017.10.039 |
| Popis: | Neuropilin-1 (NRP-1) is an extra-cellular receptor for the main Vascular Endothelial Growth Factor over-expressed in tumour tissues, VEGF-A165. Consequently, NRP-1 is involved in angiogenesis and in tumour growth, and its over-expression is related to a clinical poor prognosis. NRP-1 appears as a major target in oncology, which remains poorly exploited. Herein, we report a new series of 18 small-sized fully organic VEGF-A165/NRP-1 antagonists (NRPas). These compounds share an original scaffold, including two linkers (sulphonamide and amide) and three aromatic cores. Among them, 2a (renamed NRPa-308) emerges as a promising “hit”. In vitro, 2a exerts not only potent anti-angiogenic activity, but also significant effects on cell viability of large panel of human solid and haematological cancer cell lines. Importantly, 2a is less cytotoxic on healthy tissues than the marketed anti-angiogenic drug sunitinib. Lastly, in a mouse xenograft model (human MDA-MB-231 breast cancer cells), 2a improves the median survival and reduces the tumour growth, but does not exert visible acute toxicity. Altogether, these results highlight its huge potential for a further “hit-to-lead” optimization, leading to new anti-cancer drugs. |
| Databáze: | OpenAIRE |
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