CRM1 Blockade by Selective Inhibitors of Nuclear Export (SINE) attenuates Kidney Cancer Growth.

Comparative Pathology Graduate Group, University of California, Davis, CA, USA, 95616.
The Journal of urology (Impact Factor: 4.47). 10/2012; 189(6). DOI: 10.1016/j.juro.2012.10.018
Source: PubMed


Renal cell carcinoma often presents asymptomatically and patients are commonly diagnosed at the metastatic stage, when treatment options are limited and survival is poor. Since progression-free survival using current therapy for metastatic renal cell carcinoma is only 1 to 2 years and existing drugs are associated with a high resistance rate, new pharmacological targets are needed. We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma.

Materials and methods:
We tested the efficacy of the CRM1 inhibitors KPT-185 and 251 in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model. Apoptosis and cell cycle arrest were quantified and localization of p53 family proteins was assessed using standard techniques.

KPT-185 attenuated CRM1 and showed increased cytotoxicity in renal cell carcinoma cells in vitro with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused p53 and p21 to remain primarily in the nucleus in all renal cell carcinoma cell lines, suggesting that the mechanism of action of these compounds depends on tumor suppressor protein localization. Furthermore, when administered orally in a high grade renal cell carcinoma xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on target effects and no obvious toxicity.

The CRM1 inhibitor protein family is a novel therapeutic target for renal cell carcinoma that deserves further intensive investigation for this and other urological malignancies.

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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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    • "The CRM1 inhibitors KPT-185 and KPT-251 were tested in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model (i.e., Caki-1 cells were transplanted subcutaneously into athytic Nu/Nu mice). Compared to sorafenib, the SINE compounds exhibited better tumor growth inhibition and apparent sequestration of p53 and p21 in the nucleus, as well as a decrease in CRM1 protein expression, in vitro and in vivo (Inoue et al., 2013). "
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    ABSTRACT: Nucleocytoplasmic trafficking of proteins/RNAs is essential to normal cellular function. Indeed, accumulating evidence suggests that cancer cells escape anti-neoplastic mechanisms and benefit from pro-survival signals via the dysregulation of this system. The nuclear exporter chromosome region maintenance 1 (CRM1) protein is the only protein in the karyopherin-β protein family that contributes to the trafficking of numerous proteins and RNAs from the nucleus. It is considered to be an oncogenic, anti-apoptotic protein in transformed cells, since it reportedly functions as a gatekeeper for cell survival, including affecting p53 function, and ribosomal biogenesis. Furthermore, abnormally high expression of CRM1 is correlated with poor patient prognosis in various malignancies. Therapeutic targeting of CRM1 has emerged as a novel cancer treatment strategy, starting with a clinical trial with leptomycin B, the original specific inhibitor of CRM1, followed by development of several next-generation small molecules. KPT-330, a novel member of the CRM1-selective inhibitors of nuclear export (SINE) class of compounds, is currently undergoing clinical evaluation for the therapy of various malignancies. Results from these trials suggest that SINE compounds may be particularly useful against hematological malignancies, which often become refractory to standard chemotherapeutic agents. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 06/2015; 153. DOI:10.1016/j.pharmthera.2015.06.001 · 9.72 Impact Factor
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    • "Recently, novel, orally bioavailable, small molecule, drug-like, selective inhibitors of XPO1 mediated nuclear (SINE) have been described [155]. SINE compounds bind irreversibly to the Cys528 NES recognizing residue in XPO1 and block its ability to bind to cargo proteins [156]. SINE have been shown to potently inhibit the growth of multiple cancer cell lines and animal tumor models such as acute myeloid leukemia [157], mantle cell lymphoma [158], and other hematological malignancies [159]. "
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    ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Seminars in Cancer Biology 03/2015; ePub ahead of print. DOI:10.1016/j.semcancer.2015.03.001 · 9.33 Impact Factor
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