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Sensitizing glioma cells to cisplatin by abrogating the p53 response with antisense oligonucleotides
Kamal Datta1, Preeti Shah, Tapasya Srivastava
1Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029.
Abstract:
Most gene therapy strategies related to p53 concentrate on the restoration of the activity of mutant p53, as several observations indicate that tumors and cell lines having the mutant gene are resistant to chemotherapy. However, as there is also some evidence to the contrary, we studied the relationship of the p53 status to the cellular response of glioma cells that were exposed to cisplatin. At a concentration of 2.5 microg/ml (which is about half the peak pharmacological blood level reached during chemotherapy), U373MG glioma cells, which had a mutant p53 gene, were more sensitive to the drug as compared to U87MG glioma cells (with normal p53). The U373MG cells responded with apoptosis while U87MG cells responded with a G2-M arrest. In U87MG cells, blocking the p53 response by antisense oligonucleotides also sensitized the cells to 2.5 microg/ml cisplatin, and shifted the cellular response from arrest to caspase 3-mediated apoptosis. A sensitive, p53-independent, mechanism for chemotherapy-induced apoptosis suggests that, in some cases, p53 abrogation by gene therapy or small molecule-based strategies could be a viable therapeutic strategy.
Insights
Glioma cells with mutant p53 showed increased sensitivity to cisplatin, undergoing apoptosis. Blocking p53 in normal p53 cells also sensitized them to cisplatin, suggesting p53 abrogation as a potential gene therapy strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gene therapy for p53 mutations often aims to restore function, as mutant p53 is linked to chemotherapy resistance.
- However, conflicting evidence suggests p53 status may influence cellular response to chemotherapy differently.
Purpose of the Study:
- To investigate the relationship between p53 status and the cellular response of glioma cells to cisplatin treatment.
- To explore the potential of p53 abrogation as a therapeutic strategy.
Main Methods:
- Exposure of U373MG (mutant p53) and U87MG (normal p53) glioma cells to cisplatin at 2.5 microg/ml.
- Inhibition of p53 response in U87MG cells using antisense oligonucleotides.
Main Results:
- U373MG cells with mutant p53 were more sensitive to cisplatin than U87MG cells with normal p53.
- U373MG cells underwent apoptosis, while U87MG cells exhibited G2-M arrest.
- Blocking p53 in U87MG cells sensitized them to cisplatin and induced apoptosis via caspase 3.
Conclusions:
- A p53-independent mechanism for chemotherapy-induced apoptosis exists in glioma cells.
- p53 abrogation strategies, including gene therapy, may be viable for enhancing chemotherapy efficacy in certain cancers.
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