CDK Inhibitors Roscovitine And CR8 Trigger Mcl-1 Down-Regulation And Apoptotic Cell Death In Neuroblastoma Cells  

Oleh:

Bettayeb, Karima ; Baunbæk, Dianne ; Delehouze, Claire ; Loaëc, Nadège ; Hole, Alison J. ; Baumli, Sonja ; Endicott, Jane A. ; Douc-Rasy, Setha ; Bénard, Jean ; Oumata, Nassima ; Galons, Hervé ; Meijer, Laurent

Jenis: Article from Article
Dalam koleksi: Genes and Cancer vol. 1 no. 4 (May 2010), page 369-380.
Topik: Neuroblastoma; Mcl-1; Cyclin-Dependent Kinase; Roscovitine; CR8
Fulltext: 369.full.pdf (748.13KB)

Isi artikel

Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC50 values: 24.2 µM and 0.4 µM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid downregulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 downregulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB.

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