The dual inhibitor of the phosphoinositol-3 and PIM kinases, IBL-202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment
| Autor: | Kyle Crassini, Yandong Shen, O. Giles Best, Michael O'Neill, Richard I. Christopherson, Stephen P. Mulligan, Michael O'Dwyer |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Integrin alpha4 Receptors Antigen B-Cell CD49d CXCR4 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 immune system diseases Cell Movement hemic and lymphatic diseases Tumor Cells Cultured Tumor Microenvironment Cytotoxic T cell Bruton's tyrosine kinase Humans Protein Kinase Inhibitors Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Quinazolinones biology Kinase Chemistry Drug Synergism Hematology Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology Cell culture Purines 030220 oncology & carcinogenesis Ibrutinib Cancer research biology.protein Idelalisib |
| Zdroj: | British journal of haematology. 182(5) |
| ISSN: | 1365-2141 |
| Popis: | Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance. |
| Databáze: | OpenAIRE |
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