Abstract
The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment of onco-hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed, based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3 loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB). NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3 in promoting both induction of apoptosis and cell cycle arrest in p53wild-type JVM-2 cells, but not in p53mutated BJAB cells. Moreover, injection of NP-Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural characteristics of the NP-Nutlin-3, as well as their biological activity in vitro and in vivo, made them promising for further preclinical evaluations as potentially useful anti-leukemic carriers.
Keywords: PLGA nanoparticles, B-cell leukemia, nutlin-3, p53, apoptosis, cell cycle.
Current Medicinal Chemistry
Title:Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells
Volume: 20 Issue: 21
Author(s): R. Voltan, P. Secchiero, B. Ruozi, L. Caruso, F. Forni, M. Palomba, G. Zauli and M.A. Vandelli
Affiliation:
Keywords: PLGA nanoparticles, B-cell leukemia, nutlin-3, p53, apoptosis, cell cycle.
Abstract: The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment of onco-hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed, based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3 loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB). NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3 in promoting both induction of apoptosis and cell cycle arrest in p53wild-type JVM-2 cells, but not in p53mutated BJAB cells. Moreover, injection of NP-Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural characteristics of the NP-Nutlin-3, as well as their biological activity in vitro and in vivo, made them promising for further preclinical evaluations as potentially useful anti-leukemic carriers.
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Voltan R., Secchiero P., Ruozi B., Caruso L., Forni F., Palomba M., Zauli G. and Vandelli M.A., Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells, Current Medicinal Chemistry 2013; 20 (21) . https://dx.doi.org/10.2174/0929867311320210007
DOI https://dx.doi.org/10.2174/0929867311320210007 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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