title: Inhibition of phosphatidylinositol-3-kinase synergizes with gemcitabine in low-passage tumor cell lines correlating with Bax translocation to the mitochondria.
abstract: Apoptotic pathways, including the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway, are altered in most cancer cells in relation to their normal counterparts and these differences may present an excellent therapeutic window. To gain insight into the relevance of the PI3K pathway as a target for drug discovery we generated tumor cell lines from different tumor samples that we maintained at low passage. The characterization of these cell lines indicates that all of them have constitutively activated the PI3K pathway through different mechanisms. All cell lines were differentially sensitive to the PI3K inhibitor LY294002. Our data also support previous work indicating that PI3K inhibition might help classical chemotherapeutic treatments such as gemcitabine and strengthen suboptimal doses that might be effective for these purposes in decreasing the risk of side-effects. Finally, the analysis of the molecular markers that might be implicated in the synergism between LY294002 and gemcitabine suggests that PI3K inhibition might aid chemotherapeutic treatment, leading to changes in the balance between anti- and pro-apoptotic molecules of the Bcl-2 family, Bcl-XL and Bax. These results facilitate the exploration of potential synergism between chemotherapeutic treatment and the search for others that can account for similar molecular mechanisms of cooperation.
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.forename: Belen
authors.initials: B
authors.lastname: Pequeño
authors.forename: Victoria
authors.initials: V
authors.lastname: Moneo
authors.forename: Lourdes
authors.initials: L
authors.lastname: Romero
authors.forename: Juan F M
authors.initials: JF
authors.lastname: Leal
authors.forename: Juan
authors.initials: J
authors.lastname: Velasco
authors.forename: Jesús
authors.initials: J
authors.lastname: Fominaya
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D020128:Inhibitory Concentration 50; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003841:Deoxycytidine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000093542:Gemcitabine