The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance.
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-kappaB/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-kappaB 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.
Cilloni
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Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy. daniela.cilloni@unito.it
Messa
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Arruga
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F
Defilippi
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I
Morotti
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A
Messa
E
E
Carturan
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S
Giugliano
E
E
Pautasso
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M
Bracco
E
E
Rosso
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Sen
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Martinelli
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G
Baccarani
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Saglio
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001665:Binding Sites; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay / Q000379:methods
D000970:Antineoplastic Agents; D001549:Benzamides; D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004247:DNA; D051550:I-kappa B Kinase