Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma

Abstract

Gliomas are primary brain tumors with poor prognosis that exhibit frequent abnormalities in phosphatidylinositol 3-kinase (PI3 kinase) signaling. We investigated the molecular mechanism of action of the isoform-selective class I PI3 kinase and mTOR inhibitor PI-103 in human glioma cells. The potent inhibitory effects of PI-103 on the PI3 kinase pathway were quantified. PI-103 and the mTOR inhibitor rapamycin both inhibited ribosomal protein S6 phosphorylation but there were clear differences in the response of upstream components of the PI3 kinase pathway, such as phosphorylation of Thr(308)-AKT, that were inhibited by PI-103 but not rapamycin. Gene expression profiling identified altered expression of genes encoding regulators of the cell cycle and cholesterol metabolism, and genes modulated by insulin or IGF1 signaling, rapamycin treatment or nutrient starvation. PI-103 decreased expression of positive regulators of G(1)/S phase progression and increased expression of the negative cell cycle regulator p27(kip1). A reversible PI-103-mediated G(1) cell cycle arrest occurred without significant apoptosis, consistent with the altered gene expression detected. PI-103 induced vacuolation and processing of LC-3i to LC-3ii, which are features of an autophagic response. In contrast to PI-103, LY294002 and PI-387 induced apoptosis, indicative of likely off-target effects. PI-103 interacted synergistically or additively with cytotoxic agents used in the treatment of glioma, namely vincristine, BCNU and temozolomide. Compared to individual treatments, the combination of PI-103 with temozolomide significantly improved the response of U87MG human glioma xenografts. Our results support the therapeutic potential for PI3 kinase inhibitors with a PI-103-like profile as therapeutic agents for the treatment of glioma.

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

“…There are so far only few studies using PI3K inhibitors as chemosensitizers, for example in T-cell acute lymphoblastic leukemia (Chiarini et al, 2009), glioblastoma (Guillard et al, 2009;Westhoff et al, 2009) or chronic lymphocytic leukemia (Niedermeier et al, 2009), and little is yet known about the underlying molecular mechanisms of sensitization. Thus, the novelty of our study resides in particular in the elucidation of the molecular events mediating the cooperative cytotoxicity of the recently developed PI3K inhibitor PI103 and anticancer drugs, such as Doxorubicin, by demonstrating that chemosensitization by PI103 critically depends on mitochondrial outer membrane permeabilization as the result of a shift towards pro-apoptotic Bcl-2 proteins.…”

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…1,2 The prognosis of patients with GBM is very poor, mainly because it remains therapeutic challenge, and the conventional postsurgical chemotherapeutic agents exhibit limited effects. 3,4 Temozolomide (TMZ), as currently the most promising chemotherapeutic drug, is applied to treat malignant glioma, including GBM.…”

Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

“…PI-103 is a potent and selective inhibitor of class I phosphatidylinositide 3-kinases, and also of mTOR and DNA-PK, which blocked the proliferation of human cancer cells in vitro and caused pharmacodynamic biomarker effects consistent with target inhibition (29)(30)(31). PI-103 showed therapeutic activity against a range of human tumor xenografts, exhibiting inhibition of angiogenesis, invasion, and metastasis, as well as direct antiproliferative effects (29,31,32).…”

“…With our collaborators Hayakawa et al (25)(26)(27)(28), we have previously reported the discovery of three new series of phosphatidylinositide 3-kinase inhibitors and described the detailed pharmacologic properties of a novel synthetic lead compound of the tricyclic pyridofuropyrimidine class, PI-103 (29,30). PI-103 is a potent and selective inhibitor of class I phosphatidylinositide 3-kinases, and also of mTOR and DNA-PK, which blocked the proliferation of human cancer cells in vitro and caused pharmacodynamic biomarker effects consistent with target inhibition (29)(30)(31).…”