Ubiquitin-proteasome system is a sensitive target in
Ph+ leukemia
Martinelli G,1 Cilloni D2, Rosti
G1, Piccaluga P, Rondoni M, Bosi C , Paolini S, Pane
F3, Soverini S1
Amabile M1, Nadali G4, Izzo B3,
Iacobucci I1, Poerio S1, Terragna
C1, Ottaviani E1, Grafone T1
De Vivo A1, Testoni N1, Saglio G2,
Baccarani M1
1Institute of Hematology
and Medical Oncology “L. and A. Seràgnoli”,
University of Bologna;
2Division of Hematology and Internal Medicine,
Department of Clinical and Biological
Science, University of Turin; 3CEINGE Biotecnologie
Avanzate and Department of Biochemistry and Medical Biotechnology,
University of Naples Federico II; 4Dipartimento di
Medicina Clinica e Sperimentale, Sezione di
Ematologia, Università e Azienda Ospedaliera di Verona,
Italy
The ubiquitin-proteasome system is an attractive target for anticancer drug development in several cancer including Chronic Myeloid Leukemia Ph+ (CML). The Bcr/Abl tyrosine kinase, the hallmark of CML, by multiple signaling/survival pathways downstream, including the ubiquitin-proteasome system, contributes to leukemic transformation Several key proteins that regulate important cellular processes such as proliferation and apoptosis are regulated by proteasome-dependent proteolysis. For these reasons, proteasome inhibitors represent a relatively new class of antineoplastic agents that act by interfering with the catalytic 20S core of the proteasome, thereby preventing the elimination of diverse cellular proteins targeted for degradation, including BCR-ABL. There are several classes of proteasome inhibitors including peptide aldehydes such as MG-132, the dipeptidyl boronic acid bortezomib, etc, with increased interest in the clinical development. Currently, the clinical utility of proteasome inhibitors in leukemia in general, and in CML in particular, remains relatively unexplored In this review we explore the molecular basis for use of this drugs in CML and the preliminary clinical utility of proteasome inhibitors in CML. [>Read full article in PDF]