Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia
- University of Coimbra, FMUC, Laboratory of Oncobiology and Hematology and University Clinic of Hematology, Faculty of Medicine (Portugal)
- University of Coimbra, Centre for Functional Ecology (CFE), Department of Life Sciences (Portugal)
- Centro Hospitalar Universitário de Coimbra (CHUC), Clinical Hematology Department (Portugal)
- FMUC, Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO) (Portugal)
- Hospital da Luz (Portugal)
Although Imatinib and other tyrosine kinase inhibitors (TKIs) have excellent results, the appearance of resistance is a problem in chronic myeloid leukaemia (CML). PI3K/AKT/mTOR pathway is activated by BCR-ABL playing a crucial rule in CML. This study aimed to evaluate the therapeutic potential of Everolimus, in CML models sensitive and resistant to Imatinib. We used one CML cell line sensitive to Imatinib (K562) and two resistant (K562-RC and K56-RD). Cell lines were treated with Everolimus alone and in combination with Imatinib. Cell viability was analysed by resazurin assay. Cell death and cell cycle were analysed by flow cytometry. Additionally, we also studied peripheral blood samples obtained from 52 patients under TKI treatment. Everolimus reduced cell line viability in sensitive (IC{sub 50} = 20 µM) and resistant models (K562-RC, IC{sub 50} = 25 µM; K562-RD, IC{sub 50} = 30 µM). This drug induced cell death by apoptosis and cell cycle arrest in G{sub 0}/G{sub 1} phase. Everolimus also reduced cell viability by increasing apoptosis of haematopoietic stem cells (CD34{sup +} cells) with low cytotoxicity to lymphocytes. Everolimus at 25 µM increased apoptotic cells 18.7% in CD34{sup +} cells and only 8% in lymphocytes. The response to Everolimus was influenced by TKI treatment, with a better response in samples from patients under 2nd and 3rd generation TKI and with less toxicity to lymphocytes. Our results reveal that Everolimus induce cell death in CML cells sensitive and resistant to Imatinib, with low cytotoxicity to normal cells, suggesting that Everolimus could be an alternative targeted therapeutic approach in CML patients, even in cases of Imatinib resistance.
- OSTI ID:
- 22938434
- Journal Information:
- Medical Oncology (Online), Vol. 36, Issue 3; Other Information: Copyright (c) 2019 Springer Science+Business Media, LLC, part of Springer Nature; http://www.springer-ny.com; Country of input: International Atomic Energy Agency (IAEA); ISSN 1559-131X
- Country of Publication:
- United States
- Language:
- English
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