1. ¹Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy
2. ²Section of Cell Biology, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy
3. ³Millennium Pharmaceuticals, Cambridge, MA, USA
4. ⁴Institute of Hematology and Medical Oncology 'L and A Seràgnoli', University of Bologna, Bologna, Italy

Correspondence: Dr D Cilloni, Department of Clinical and Biological Sciences of the University of Turin, San Luigi Hospital, Gonzole 10, 10043 Orbassano-Torino, Italy. E-mail: daniela.cilloni@unito.it

Received 20 January 2005; Revised 15 September 2005; Accepted 19 September 2005; Published online 3 November 2005.

Abstract

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-B/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-B activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.