Controlling Protein Transport by Small Molecules

Gademann, Karl

doi:10.2174/138945011798109446

Cited by 18 publications

(15 citation statements)

References 45 publications

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“…For this purpose, we treated cells with leptomycin B (LMB), an inhibitor of the nuclear export receptor CRM1. 24 As shown in Figure 5A (top panels), without LMB treatment, Ubp-M was predominately localized to the cytoplasm during interphase. After LMB treatment, we found that a significant number of cells retained Ubp-M in the nucleus (Fig.…”

Section: S552p Regulates the Interaction Between Ubp-m And Crm1mentioning

confidence: 80%

Ubp-M serine 552 phosphorylation by cyclin-dependent kinase 1 regulates cell cycle progression

Yang

Joo

et al. 2013

Cell Cycle

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Section: S552p Regulates the Interaction Between Ubp-m And Crm1mentioning

confidence: 80%

Ubp-M serine 552 phosphorylation by cyclin-dependent kinase 1 regulates cell cycle progression

Yang

Joo

et al. 2013

Cell Cycle

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“…Anguinomycin C and D have been reported to be cytotoxic selectively against transformed cell lines, while only inducing cytostatic effects in normal cells. Immunostaining of the Rio2 kinase in HeLa cells showed that anguinomycin C and D inhibit nucleocytoplasmic transport at a concentration of less than 10nM (Bonazzi, et al, 2007; Gademann, 2011). This indicates that these compounds are able to block the CRM1 mediated nuclear export at levels comparable to leptomycin B itself.…”

Section: Inhibitors Of the Crm1 Proteinmentioning

confidence: 99%

“…Goniothalamin is the parent member of a class of styryl lactones that are extracted from different species of plants of the genus Goniothalamus (Gademann, 2011; Jewers, Burbage, Blunden, & Griffin, 1974). In an in vivo nuclear export assay, the immunostaining of Rio2 in HeLa cells demonstrated that goniothalamin is an inhibitor of nucleocytoplasmic transport above 500 nM.…”

Section: Inhibitors Of the Crm1 Proteinmentioning

confidence: 99%

Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein

Ishizawa

Kojima

Hail

et al. 2015

Pharmacology & Therapeutics

106

104

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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.

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“…Unfortunately, LMB's off-target effects render it inappropriate for therapeutic use (17,19). Given these constraints and therapeutic potential, a number of different classes of Selective Inhibitors of Nuclear Export (SINE) have been synthesized and are being evaluated for therapeutic efficacy (4,5,20). KPT-185 and KPT-330 (generic name: selinexor) represent two SINE compounds that potently, selectively, and covalently inhibit XPO1.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Chen

Camacho

Silvers

et al. 2017

Clinical Cancer Research

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Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexortreated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer.

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Controlling Protein Transport by Small Molecules

Cited by 18 publications

References 45 publications

Ubp-M serine 552 phosphorylation by cyclin-dependent kinase 1 regulates cell cycle progression

Ubp-M serine 552 phosphorylation by cyclin-dependent kinase 1 regulates cell cycle progression

Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

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