Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma.
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.
Guillard
Sandrine
S
Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
Clarke
Paul A
PA
Te Poele
Robert
R
Mohri
Zahra
Z
Bjerke
Lynn
L
Valenti
Melanie
M
Raynaud
Florence
F
Eccles
Suzanne A
SA
Workman
Paul
P
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
D002867:Chromones; D004791:Enzyme Inhibitors; D005663:Furans; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C522973:PI103; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one