Journal
ONCOTARGET
Volume 5, Issue 2, Pages 375-385Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1568
Keywords
CLL; cdk9; synergy; MCL1
Categories
Funding
- Cancer Research UK [C21568/A8988, C21568/A12474]
- Leukaemia and Lymphoma Research UK [10003]
- Leukaemia Research Appeal for Wales
- Cancer Research UK [17648] Funding Source: researchfish
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Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed > 200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics.
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