Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Division of Hematology, Department of Medicine, The Ohio State University, Columbus 43210, USA.
Blood (Impact Factor: 10.45). 06/2012; 120(9):1765-73. DOI: 10.1182/blood-2012-04-423160
Source: PubMed


Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500 nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.

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Available from: Parvathi Ranganathan, Nov 18, 2015
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    • "However, the effect of XPO1 inhibition on PEL has not been studied. Recently selective inhibitors of the exportin-1 (XPO1) mediated nuclear export (SINE) were found to have great potential against various solid and hematological cancers in in vitro as well as in vivo models of NHL and other hematological malignancies (Etchin et al., 2013a,b; Inoue et al., 2013; Lapalombella et al., 2012; Tai et al., 2014; Zhang et al., 2013; Ranganathan et al., 2012; Kojima et al., 2013). SINE are orally bioavailable optimized analogues of the N-azolylacrylate small-molecule inhibitors affecting XPO1-mediated nuclear export (Van Neck et al., 2008; Daelemans et al., 2002). "
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    ABSTRACT: Infection with human immunodeficiency virus (HIV) compromises the body's immune system leaving infected individuals vulnerable to other pathologies including cancer. Some forms of cancer typically develop in AIDS patients, as for example the very aggressive and most often deadly primary effusion lymphoma (PEL). There is currently no standard treatment for PEL but the use of anti-HIV drugs is associated with better prognosis. Here we show in preclinical tests that inhibitors of nuclear export suppress both HIV replication as well as PEL progression. These findings provide a rationale for further evaluating these inhibitors as treatment strategy for dual HIV/lymphoma therapy.
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    • "Previous studies showed that LMB induced p53 activation, suggesting this was the key to inducing growth arrest associated with apoptosis in prostate cancers (Lecane et al, 2003), neuroblastomas (Smart et al, 1999), and melanoma (Pathria et al, 2012). Recently, a study showed that p53 was a critical mediator of KPT-induced differentiation and apoptosis of acute myeloid leukaemia cells (Ranganathan et al, 2012). Interestingly, we observed that KPT-330 induced apoptosis in both p53-wt and -mut NSCLC cells. "
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    • "Unlike, Leptomycin B that form an irreversible covalent bond with Cys528 of CRM1, KPT-185 bind to CRM1 in a slowly reversible fashion, which might contribute to the improved tolerability of the SINE compounds. SINE block nuclear export of TSPs thereby inducing growth inhibition and apoptosis specifically in cancer cells [20,21,22,23,24,25,26,27,28]. Earlier, our group has studied the impact of CRM1 inhibtion in PDAC models and the downstream signaling analysis [13]. "
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