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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor
Barbara Costa1, Sara Bendinelli, Pamela Gabelloni
1Department of Pharmacy, University of Pisa, Pisa, Italy.
Abstract:
Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients.
Insights
A new drug, ISA27, reactivates the p53 tumor suppressor by inhibiting MDM2. This effectively stops glioblastoma multiforme (GBM) growth and shows promise as a safe, novel cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- p53 tumor suppressor dysfunction is key in cancer and chemoresistance.
- In glioblastoma multiforme (GBM), MDM2 protein inhibits p53, reducing its effectiveness.
- MDM2 inhibitors are a potential cancer treatment, but their efficacy in GBM is unclear.
Purpose of the Study:
- To investigate the efficacy of a novel MDM2 inhibitor, ISA27, in glioblastoma multiforme (GBM).
- To assess ISA27's impact on p53 reactivation, cell growth, and apoptosis in GBM.
- To evaluate ISA27's safety and synergistic effects with temozolomide (TMZ) in GBM.
Main Methods:
- Testing ISA27, a small-molecule MDM2 inhibitor, on human GBM cells in vitro.
- Administering ISA27 to mice with human GBM xenografts to assess in vivo effects.
- Evaluating ISA27's toxicity in normal human cells and mouse models.
- Assessing the combined effect of ISA27 and temozolomide (TMZ) on GBM cell viability.
Main Results:
- ISA27 reactivated p53, induced cell cycle arrest and apoptosis, inhibiting GBM cell growth in vitro.
- In vivo, ISA27 activated p53, reduced tumor proliferation, and induced apoptosis in GBM xenografts.
- ISA27 demonstrated no toxicity in normal human cells or mouse models.
- Combining ISA27 with TMZ showed synergistic inhibition of GBM cell viability.
Conclusions:
- ISA27 effectively reactivates p53 and exhibits potent antitumor activity against GBM.
- ISA27 is a non-toxic agent with potential for combination therapy, possibly reducing TMZ dosage.
- ISA27 represents a promising novel therapeutic strategy for glioblastoma multiforme patients.
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