title: Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells.
abstract: Imatinib induces a complete cytogenetic regression in a large percentage of patients affected by chronic myeloid leukemia (CML) until mutations in the kinase domain of BCR-ABL appear. Alternative strategies for CML patients include the inhibition of phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, which is constitutively activated in leukemia cells and seems important for the regulation of cell proliferation, viability, and autophagy. In this study, we verified the effect of imatinib mesylate (IM), alone or in association with LY294002 (LY) (a specific PI3K protein tyrosine kinase inhibitor) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) (a Src tyrosine kinase inhibitor), on viability, intracellular calcium mobilization, apoptosis, and autophagy, in order to verify possible mechanisms of interaction. Our data demonstrated that PP1 and LY interact synergistically with IM by inducing apoptosis and autophagy in Bcr/Abl+ leukemia cells and this mechanism is related to the stress of the endoplasmic reticulum (ER). Our findings suggest a reasonable relationship between apoptotic and autophagic activity of tyrosine kinase inhibitors (TKIs) and the functionality of smooth ER Ca (2+)-ATPase and inositol triphosphate receptors, independently of intracellular calcium levels. Therapeutic strategies combining imatinib with PI3K and/or Src kinase inhibitors warrant further investigations in Bcr/Abl+ malignancies, particularly in the cases of imatinib mesylate-resistant disease.
authors: Department of Veterinary Medicine and Animal Production; Sections of Pharmacology and Infectious Diseases; University of Naples "Federico II"; Naples, Italy.
authors: Roberto
authors: R
authors: Ciarcia
authors: Sara
authors: S
authors: Damiano
authors: Serena
authors: S
authors: Montagnaro
authors: Ugo
authors: U
authors: Pagnini
authors: Antonio
authors: A
authors: Ruocco
authors: Giuseppe
authors: G
authors: Caparrotti
authors: Danila
authors: D
authors: d'Angelo
authors: Silvia
authors: S
authors: Boffo
authors: Fátima
authors: F
authors: Morales
authors: Flavio
authors: F
authors: Rizzolio
authors: Salvatore
authors: S
authors: Florio
authors: Antonio
authors: A
authors: Giordano
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004357:Drug Synergism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007295:Inositol Phosphates / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D001549:Benzamides; D002867:Chromones; D007295:Inositol Phosphates; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C052128:inositol 3-phosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004533:Egtazic Acid; D019284:Thapsigargin; D000068877:Imatinib Mesylate; D058539:Phosphatidylinositol 3-Kinase; D019061:src-Family Kinases; D002118:Calcium
keywords: PI3K inhibitor; Src kinase inhibitor; apoptosis; autophagy; chronic myeloid leukemia; imatinib mesylate; intracellular calcium [Ca2+]i
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