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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Evidence That a Peptide-Drug/p53 Gene Complex Promotes Cognate Gene Expression and Inhibits the Viability of
Ana Neves1, Tânia Albuquerque1, Rúben Faria1
1CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-001 Covilhã, Portugal.
Abstract:
Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Conventional therapies are followed by poor patient survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Gene therapy has emerged as an exciting and innovative tool in cancer therapy. Its combination with chemotherapy has significantly improved therapeutic outcomes. In line with this, our team has developed temozolomide-transferrin (Tf) peptide (WRAP5)/p53 gene nanometric complexes that were revealed to be biocompatible with non-cancerous cells and in a zebrafish model and were able to efficiently target and internalize into SNB19 and U373 glioma cell lines. The transfection of these cells, mediated by the formulated peptide-drug/gene complexes, resulted in p53 expression. The combined action of the anticancer drug with p53 supplementation in cancer cells enhances cytotoxicity, which was correlated to apoptosis activation through quantification of caspase-3 activity. In addition, increased caspase-9 levels revealed that the intrinsic or mitochondrial pathway of apoptosis was implicated. This assumption was further evidenced by the presence, in glioma cells, of Bax protein overexpression-a core regulator of this apoptotic pathway. Our findings demonstrated the great potential of peptide TMZ/p53 co-delivery complexes for cellular transfection, p53 expression, and apoptosis induction, holding promising therapeutic value toward glioblastoma.
Insights
Novel peptide-drug/gene complexes show promise for glioblastoma treatment. These complexes deliver chemotherapy and p53 gene, enhancing cancer cell death via apoptosis and offering new therapeutic avenues.
Area of Science:
- Oncology
- Gene Therapy
- Nanomedicine
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor patient survival.
- Conventional therapies for GBM have limited efficacy, necessitating novel treatment strategies.
- Gene therapy combined with chemotherapy offers a promising approach for improved GBM treatment outcomes.
Purpose of the Study:
- To develop and evaluate novel nanometric complexes for co-delivery of temozolomide (chemotherapy) and p53 gene for glioblastoma treatment.
- To assess the biocompatibility, targeting, and internalization efficiency of these complexes in glioma cell lines.
- To investigate the therapeutic potential of these complexes in inducing apoptosis and enhancing cytotoxicity in glioblastoma cells.
Main Methods:
- Formulation of temozolomide-transferrin (Tf) peptide (WRAP5)/p53 gene nanometric complexes.
- Evaluation of complex biocompatibility in non-cancerous cells and a zebrafish model.
- Assessment of cellular targeting and internalization in SNB19 and U373 glioma cell lines.
- Quantification of p53 expression, caspase-3 and caspase-9 activity, and Bax protein levels to determine apoptosis induction.
Main Results:
- The developed nanometric complexes demonstrated biocompatibility and efficient targeting and internalization into glioma cells.
- Transfection with the complexes led to significant p53 gene expression in cancer cells.
- Combined chemo-gene therapy significantly enhanced cytotoxicity, inducing apoptosis through both caspase-3 and caspase-9 activation.
- Upregulation of Bax protein confirmed the involvement of the intrinsic mitochondrial apoptotic pathway.
Conclusions:
- Peptide-based nanometric complexes enable effective co-delivery of chemotherapy and p53 gene for glioblastoma.
- These complexes hold significant therapeutic potential by promoting p53 expression and inducing apoptosis in glioma cells.
- The findings support the development of this novel therapeutic strategy for glioblastoma treatment.
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