Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma

Abstract

The phosphoinositide 3 ¶-kinase (PI3K) -mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110A inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110B inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin.

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

“…1). Our results corroborate findings from a recent study that revealed the higher efficacy of several smallmolecule inhibitors of PI3K in radiosensitizing glioma cells lacking wild-type PTEN (22). Of importance, not only caffeine but also the less toxic pentoxifylline selectively radiosensitized PTEN-deficient glioma cells (Table 1B), supporting the clinical relevance of our finding.…”

“…1). Our study further supports the important role of Akt rather than ATM/ATR in caffeinemediated radiosensitization of PTEN-deficient glioma cells, and thereby corroborate conclusions from previous reports (19,22) and a very recent study (25) that Akt represents an important therapeutic target in combination with IR in the treatment of PTEN-deficient brain tumors.…”

A novel dual PI3Kα/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells

“…The high efficacy of multitargeted intervention was previously described for NSCLC, human melanoma and other tumor types (28)(29)(30). In the present study, the dual inhibitor PI-103 indeed showed obvious antitumor activity in gefitinibresistant NSCLC cell lines as seen in glioma and other tumor cell lines, further reinforcing the importance of multitargeted therapeutics (11,31,32). Additionally, we identified that activating mutations of PIK3CA were a crucial determinant of response to low-dose PI-103.…”

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

“…Thus, our findings show that inhibition of PI3K-mediated signaling is a promising therapeutic approach to overcome resistance of GBM. This is of particular interest as a recent study by Chen et al (2008) shows a similar sensitizing effect in GBM after radiation treatment combined with PI-103 . Although the authors did not investigate the underlying mechanisms, similar pathways as those described in this study may be involved.…”