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The multi‐kinase inhibitor TG 02 overcomes signalling activation by survival factors to deplete MCL 1 and XIAP and induce cell death in primary acute myeloid leukaemia cells
Author(s) -
Pallis Monica,
AbdulAziz Amina,
Burrows Francis,
Seedhouse Claire,
Grundy Martin,
Russell Nigel
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12018
Subject(s) - xiap , kinase , cyclin dependent kinase , cell cycle , cancer research , cdk inhibitor , chemistry , phosphorylation , apoptosis , biology , programmed cell death , microbiology and biotechnology , biochemistry , caspase
Summmary The novel multi‐kinase inhibitor TG 02 has selectivity against cell cycle and transcriptional cyclin dependent kinases ( CDK s) as well as fms‐like tyrosine kinase receptor‐3 ( FLT 3). Inhibition of transcriptional CDK s preferentially depletes short‐lived proteins such as MCL 1. We evaluated the in vitro toxicity of TG 02 to primary acute myeloid leukaemia ( AML ) cells in the presence of survival signalling pathway activation by cytokines and fibronectin. One hundred nanomolar TG 02 induced a median decrease of 40% in bulk cell survival and 43% in the CD 34 + CD 38 − CD 123 + subset. A 90% inhibitory concentration of 500 nmol/l indicated that TG 02 toxicity is not halted by protective cell cycle arrest. Samples with FLT 3 internal tandem duplication were not preferentially targeted. By flow cytometry, TG 02 treatment caused loss of RNA P olymerase II serine 2 phosphorylation in patient samples, which correlated strongly with BAX activation ( R 2 =0·89), suggesting these as potential biomarkers for clinical studies. MCL 1 and XIAP expression also decreased. Repeated brief exposure to TG 02 in MOLM ‐13 cells did not result in compensatory up‐regulation of survival protein expression. In conclusion, TG 02 is potently cytotoxic towards CD 34 + CD 38 − CD 123 + and bulk AML cells, despite protective signalling pathway activation. This antitumour activity is most likely mediated by dephosphorylation of RNA P olymerase II leading to depletion of survival molecules such as MCL 1 and XIAP , with subsequent BAX activation and apoptosis.