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Nemangwele, Fhulufhelo Fisher, Randall Engelbrecht-Roberts, Monique Maluleka, Musa 2026-06-17T21:12:31Z 2026-06-17T21:12:31Z 2026-05-19 Maluleka, M. 2026. Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells. . . https://univendspace.univen.ac.za/handle/11602/3210 Maluleka M. Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells. []. , 2026 [cited yyyy month dd]. Available from: Maluleka, M. (2026). <i>Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells</i>. (). . Retrieved from Maluleka, Musa. <i>"Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells."</i> ., , 2026. TY - Dissertation AU - Maluleka, Musa AB - Medulloblastoma (MB) and glioblastoma (GB) are highly aggressive brain tumours for which treatment outcomes remain poor, particularly due to intrinsic and acquired resistance to radiotherapy. Molecular determinants, especially TP53 status, play a critical role in regulating tumour cell proliferation, cell-cycle control, and DNA damage response following irradiation. This study investigated the biological effects of the MDM2 inhibitor AMG232 in combination with photon irradiation in TP53- wild-type and TP53-mutant MB and GB cell lines, with the aim of assessing whether AMG232 enhances radiosensitivity in a TP53-dependent manner. Cell proliferation, cell-cycle distribution, and DNA damage were assessed using growth assays, flow cytometry, and H2AX foci analysis, respectively. The findings showed that TP53 status strongly influenced cellular responses to treatment. TP53-wild-type cell lines demonstrated clearer growth control following AMG232 treatment, consistent with activation of functional p53 signalling. In contrast, TP53- mutant cell lines showed slower growth, inconsistent cell-cycle regulation, and weaker responses to AMG232, indicating limited recovery of p53 function. Cell-cycle analysis revealed that AMG232 induced a stronger and more sustained G0/G1 arrest in TP53-wild-type cells, supporting activation of the canonical p53–p21 axis. TP53-mutant cells displayed only partial or transient G0/G1 accumulation, suggesting the involvement of p53-independent stress responses rather than effective checkpoint enforcement. H2AX foci analysis confirmed a dose-dependent induction of DNA DSBs following photon irradiation across all cell lines. AMG232 treatment was associated with increased persistence of H2AX foci, particularly in MB cell lines, indicating impaired or delayed DNA repair. Residual foci at later time points reflected the predominance of error-prone non-homologous end joining, especially in G0/G1-arrested cells. In GB cell lines, DNA repair efficiency remained limited irrespective of treatment, highlighting intrinsic radioresistance. This study demonstrates that AMG232 enhances radiosensitivity primarily by prolonging DNA damage signalling and reducing DNA repair capacity, with effects that are most pronounced in TP53-wild-type cell lines. These findings highlight the importance of TP53 status in determining the therapeutic efficacy of MDM2 inhibition combined with photon irradiation and support the potential for molecularly guided treatment strategies in aggressive brain tumours. DA - 2026-05-19 DB - ResearchSpace DP - Univen KW - Medulloblastoma KW - Glioblastoma KW - TP53 KW - AMG232 KW - MDM inhibition KW - Photon irradiation KW - DNA damage response KW - Radiosensitivity LK - https://univendspace.univen.ac.za PY - 2026 T1 - Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells TI - Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells UR - ER - M.Sc. in Physics Department of Physics Medulloblastoma (MB) and glioblastoma (GB) are highly aggressive brain tumours for which treatment outcomes remain poor, particularly due to intrinsic and acquired resistance to radiotherapy. Molecular determinants, especially TP53 status, play a critical role in regulating tumour cell proliferation, cell-cycle control, and DNA damage response following irradiation. This study investigated the biological effects of the MDM2 inhibitor AMG232 in combination with photon irradiation in TP53- wild-type and TP53-mutant MB and GB cell lines, with the aim of assessing whether AMG232 enhances radiosensitivity in a TP53-dependent manner. Cell proliferation, cell-cycle distribution, and DNA damage were assessed using growth assays, flow cytometry, and H2AX foci analysis, respectively. The findings showed that TP53 status strongly influenced cellular responses to treatment. TP53-wild-type cell lines demonstrated clearer growth control following AMG232 treatment, consistent with activation of functional p53 signalling. In contrast, TP53- mutant cell lines showed slower growth, inconsistent cell-cycle regulation, and weaker responses to AMG232, indicating limited recovery of p53 function. Cell-cycle analysis revealed that AMG232 induced a stronger and more sustained G0/G1 arrest in TP53-wild-type cells, supporting activation of the canonical p53–p21 axis. TP53-mutant cells displayed only partial or transient G0/G1 accumulation, suggesting the involvement of p53-independent stress responses rather than effective checkpoint enforcement. H2AX foci analysis confirmed a dose-dependent induction of DNA DSBs following photon irradiation across all cell lines. AMG232 treatment was associated with increased persistence of H2AX foci, particularly in MB cell lines, indicating impaired or delayed DNA repair. Residual foci at later time points reflected the predominance of error-prone non-homologous end joining, especially in G0/G1-arrested cells. In GB cell lines, DNA repair efficiency remained limited irrespective of treatment, highlighting intrinsic radioresistance. This study demonstrates that AMG232 enhances radiosensitivity primarily by prolonging DNA damage signalling and reducing DNA repair capacity, with effects that are most pronounced in TP53-wild-type cell lines. These findings highlight the importance of TP53 status in determining the therapeutic efficacy of MDM2 inhibition combined with photon irradiation and support the potential for molecularly guided treatment strategies in aggressive brain tumours. 1 online resource (x, 57 leaves) en PDF University of Venda Medulloblastoma Glioblastoma TP53 AMG232 MDM inhibition Photon irradiation DNA damage response Radiosensitivity UCTD Activation of the p53 pathway in combination with photon irradiation for the treatment of neurological tumour cells Dissertation embargo