Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells

Roberto Ciarcia, Sara Damiano, Serena Montagnaro, Ugo Pagnini, Antonio Ruocco, Giuseppe Caparrotti, Danila D'Angelo, Silvia Boffo, Fátima Morales, Flavio Rizzolio, Salvatore Florio, Antonio Giordano

Research output: Contribution to journalArticlepeer-review


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 Ca2+-AT Pase 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.

Original languageEnglish
Pages (from-to)2839-2848
Number of pages10
JournalCell Cycle
Issue number17
Publication statusPublished - Sep 1 2013


  • Apoptosis
  • Autophagy
  • Chronic myeloid leukemia
  • Imatinib mesylate
  • Intracellular calcium [Ca2+]i
  • PI3K inhibitor
  • Src kinase inhibitor

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology


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