1. CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme.
- Author
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Daniele S, La Pietra V, Piccarducci R, Pietrobono D, Cavallini C, D'Amore VM, Cerofolini L, Giuntini S, Russomanno P, Puxeddu M, Nalli M, Pedrini M, Fragai M, Luchinat C, Novellino E, Taliani S, La Regina G, Silvestri R, Martini C, and Marinelli L
- Subjects
- Brain Neoplasms enzymology, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Drug Synergism, Glioblastoma enzymology, Glioblastoma genetics, Glioblastoma pathology, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Neurogenesis drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Receptors, CXCR4 metabolism, Signal Transduction, Spheroids, Cellular, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzylamines pharmacology, Brain Neoplasms drug therapy, Cell Cycle Proteins antagonists & inhibitors, Cyclams pharmacology, Glioblastoma drug therapy, Indoles pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Receptors, CXCR4 antagonists & inhibitors
- Abstract
Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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