Navarra, Giovanna (2023) DEVELOPMENT OF NEW THERAPEUTIC APPROACHES TO RADIOSENSITIZE GLIOBLASTOMA CELLS. [Tesi di dottorato]

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Abstract

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults with poor prognosis due to the bad response to therapeutic regimens such as radiotherapy and chemotherapy. Ionizing radiation (IR) has been iden-tified as a crucial treatment for GBM following surgical resection to improve both local control and survival. Unfortunately, radiotherapy resistance is fre-quently observed in GBM patients, which is the main reason for the high mor-tality rate of cancer patients. Tumours typically recurs due to robust DNA re-pair, so the mechanisms underlying the intrinsic radio-resistance in GBM are rigorously studied. In the present work are investigated two different approaches to evaluate their radiosensitizer effects in GBM cells. A first study, more detailed, in which a natural molecule is used, and a second, still ongoing, in which nanotechnolo-gy is tested. Previous studies of my research group reported N6-isopentenyladenosine (iPA), a naturally modified adenosine harboring an iso-pentenyl moiety, has shown several antiproliferative effects on GBM cell lines. In this study has been shown the potential of iPA treatment at micromolar concentration, in combination with IR, enhance radiotherapy sensitivity of GBM cells. The combined treatment significantly attenuated the repair of ra-diation-induced DNA damage by inhibiting both the expression and irradia-tion-induced foci formation of RAD51, a key player in the homologous re-combination repair process, leading to persistent DNA damage, as reflected by an increase of ɣ-H2AX foci. These data suggest that iPA could function as a promising radiosensitizer agent for GBM cells. We are currently evaluating the effectiveness of new approaches such as the use of gold nanoparticles (AuNPs). AuNPs are actively under study and hold promise to improve the treatment response to radiotherapy. AuNPs, specifi-cally nanoprisms (NPrs) have been tested in two several GBM cell lines. The AuNPs act by photothermal therapy (PTT), an efficient method of inducing localized hyperthermia aiming to selectively kill tumor cells. Preliminary da-ta, show that AuNPrs at low concentrations have no toxic effects in GBM cells and when combined with different radiation doses, have an encouraging radiosensitizing effect. Therefore, it is our interest to study the synergistic ef-fects of iPA together with AuNPs in order to develop a promising strategy to extend the efficacy of radiotherapy in GBM cells.

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