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A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine

2013; Impact Journals LLC; Volume: 5; Issue: 2 Linguagem: Inglês

10.18632/oncotarget.1568

1949-2553

Elisabeth Walsby, Guy Pratt, Hao Shao, Abdullah Y. Abbas, Peter M. Fischer, Tracey D. Bradshaw, Paul Brennan, Chris Fegan, Shudong Wang, Chris Pepper,

Acute Myeloid Leukemia Research

// Elisabeth Walsby 1 , Guy Pratt 2 , Hao Shao 3 , Abdullah Y. Abbas 3 , Peter M. Fischer 3 , Tracey D. Bradshaw 3 , Paul Brennan 1 , Chris Fegan 1 , Shudong Wang 3,4 and Chris Pepper 1 1 Cardiff CLL Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. 2 CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK. 3 School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK. 4 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia. Correspondence: Chris Pepper, email: // Keywords : CLL, cdk9, synergy, MCL1 Received : November 3, 2013 Accepted : December 18, 2013 Published : December 18, 2013 Abstract 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.