Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line

Abstract

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

“…A new SRC inhibitor, belonging to the pyrazolo[3¨ -d] pyrimidines series (i.e., Si306, Lead Discovery Siena, Italy) showed an excellent pharmacodynamic profile and was able to significantly inhibit GBM cell growth in highly P-gp expressing cells as compared to dasatinib [ 116 ]. We previously demonstrated that Si306 showed a synergic radiosensitive effect with proton irradiation in GBM cell lines [ 117 ]. We also identified up- or down-regulated genes associated with the SRC pathway modulation in GBM cells after irradiation with proton therapy [ 117 ].…”

“…We previously demonstrated that Si306 showed a synergic radiosensitive effect with proton irradiation in GBM cell lines [ 117 ]. We also identified up- or down-regulated genes associated with the SRC pathway modulation in GBM cells after irradiation with proton therapy [ 117 ]. After 2 or 10 Gy irradiation with protons, we detected that the GBM cell cycle, motility, survival, and proliferation rate were strongly affected by Si306, also showing increased overall radiation efficiency [ 117 ].…”

“…We also identified up- or down-regulated genes associated with the SRC pathway modulation in GBM cells after irradiation with proton therapy [ 117 ]. After 2 or 10 Gy irradiation with protons, we detected that the GBM cell cycle, motility, survival, and proliferation rate were strongly affected by Si306, also showing increased overall radiation efficiency [ 117 ]. Moreover, Si306 has been tested in combination with X-ray both in normoxic and hypoxic conditions, demonstrating a significantly increased effect as compared to radiotherapy alone [ 30 , 118 ].…”

Local Disease-Free Survival Rate (LSR) Application to Personalize Radiation Therapy Treatments in Breast Cancer Models

“…from which we obtained the α[ ] and β[ ] parameters, extracted from the fit with their own standard deviation, and where S(0) is the zero-dose surviving fraction, obtained from a previous second-order fit, and as previously described [28].…”

A doxycycline-inducible C17.2 neural stem cell-based combination of differentiation and suicide gene therapy for an in vitro tumorigenic C6 glioma model

“…This plasmid contains the doxycycline-inducible TRE3G promoter (P TRE3G ) and a TK-green fluorescent protein (GFP) fusion protein coding sequence. Furthermore, previous studies have revealed that combination gene therapies exert additive or synergistic effects on brain tumors [15,16]. Accordingly, we have left an EcoRI cloning site of pTRE3G-TKGFP available for the insertion of other therapeutic genes to cooperate with the TK/GCV system in cancer therapy.…”