The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance

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-jB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Relblocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-jB 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.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…In addition, Bcr-Abl-induced NF-kB activation seems to involve the activation of the kinase MEK kinase 1 (MEKK1) (Nawata et al, 2003) (see Figure 2). Consistent with a role for NF-kB in Bcr-Ablassociated malignancies, NF-kB was found to be chronically active in CML and in Bcr-Abl-positive acute lymphocytic leukemias (Kirchner et al, 2003;Munzert et al, 2004;Cilloni et al, 2006). Another example of activation of NF-kB by an oncoprotein is the mechanism whereby the HTVL-1 Tax protein activates NF-kB; that is, Tax can directly bind and activate the IKK complex (Hiscott et al, 2006).…”

Deferasirox is a powerful NF- B inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging

“…41 The NF-B inhibitor PS 1145 (Millenium, Cambridge, MA, USA) was added to the medium at 20 μM as previously described. 42 Incubated and control cells were both evaluated for NF-κB activity. Unless stated otherwise, all the experiments were carried out independently three times.…”

“…Antibodies against the unrelated proteins b-actin (Sigma Aldrich, St Louis, MO, USA) or lamin (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) were used both at 1:1000 dilutions as controls. 42 Immunofluorescence assay was performed using a p65 polyclonal primary antibody (Santa Cruz Biotechnology) according to standard procedures. The signal was detected using a goat antirabbit Alexa Fluor 568 (FITC) secondary antibody (Molecular Probes) and propidium iodide to stain the nucleus.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…Two recent frontiers in leukemia research are the emergence of imatinib-resistant CMLs [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] and the discovery of mutations at the Jak2 kinase in certain myeloproliferative diseases. These topic areas document the importance of genetic approaches in leukemia and abnormal hematopoiesis research as they were discovered upon identification of the genetic mutations responsible for the hematopoietic neoplasia.…”