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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
D Sorriento1, C Del Giudice2, A Bertamino3
11] Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy [2] Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples 80145, Italy.
Background:
p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity.
Methods:
In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot.
Results:
Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth.
Conclusions:
Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity.
Insights
New compounds ISA27 and SM13 induce apoptosis in cancer cells with wild-type or mutated p53. SM13 shows promise as a treatment for p53-dependent tumors, even without p53 transcriptional activity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- p53 is a tumor suppressor that induces apoptosis.
- Newly synthesized compounds ISA27 and SM13 inhibit p53-MDM2 interaction.
- These compounds induce apoptosis in p53 wild-type (WT) tumor cells.
Purpose of the Study:
- To evaluate ISA27 and SM13 efficacy in tumors with mutated p53 lacking transcriptional activity.
- To determine if the compounds' apoptotic effects are independent of p53 transcriptional function.
Main Methods:
- In vitro testing on cancer cell lines with WT, mutated, and null p53.
- In vivo studies in Balb/c nude mice.
- Western blot analysis of mitochondrial-dependent apoptotic signaling.
Main Results:
- ISA27 and SM13 reduced proliferation and induced apoptosis in p53 WT and mutated cells in vitro.
- SM13 was ineffective in p53 null cells, indicating p53-dependence.
- In vivo, both compounds triggered apoptosis and reduced tumor growth in p53-mutated cells.
Conclusions:
- ISA27 and SM13 are effective against p53-dependent tumors.
- SM13 is a potential anticancer agent for tumors with mutated p53, irrespective of transcriptional activity.
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