p53-dependent anticancer effects of leptomycin B on lung adenocarcinoma

Shao, Changxia; Lü, Chao; Chen, Lixia; Koty, Patrick P.; Cobos, Everardo; Gao, Weimin

doi:10.1007/s00280-010-1434-6

Cited by 38 publications

(49 citation statements)

References 56 publications

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“…46 LMB is the most extensively studied XPO1 inhibitor, and is a widely used biologic tool to define XPO1-mediated protein export. LMB was shown to be active preclinically in several solid tumor and hematologic tumor models 18,19,21,42 but was associated with a low therapeutic index in mouse studies because of off-target gastrointestinal effects, as well as profound doselimiting anorexia, fatigue, and gastrointestinal effects when introduced in a phase 1 study when given intravenously. 20 In this trial neither target validation of XPO1 inhibition nor etiology of nausea/emesis and fatigue were adequately addressed.…”

Section: Discussionmentioning

confidence: 99%

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Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Lapalombella

Sun

Williams

et al. 2012

Blood

265

335

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The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of

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Section: Discussionmentioning

confidence: 99%

“…16,17 To date, efforts to clinically pharmacologically inhibit XPO1 have been unsuccessful because of off-target effects. [18][19][20][21] A selective XPO1 antagonist may allow targeting of the TSPs axes in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Lapalombella

Sun

Williams

et al. 2012

Blood

265

335

View full text Add to dashboard Cite

show abstract

“…Leptomycin B modifies CRM1 by a Michael-type covalent addition reaction at the reactive site (i.e., cysteine 528). In vitro studies have shown that leptomycin B induces acute cytotoxicity at concentration less than 5 μM for 1 h (Mutka, et al, 2009), and the agent was also active in preclinical solid and hematologic tumor models (Mutka, et al, 2009; Shao et al, 2011; Turner, et al, 2009). One of the potential clinical problems associated with leptomycin B that were discovered in preclinical tumor models was its low therapeutic index.…”

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

107

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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“…8, 9 In addition, multiple studies show that inhibition of CRM1 induces apoptosis and inhibits tumor growth in several cancer cell lines. 10, 11 However, despite abundant knowledge of subcellular TSP localization being important in RCC behavior, 12 there are no published studies of CRM1 inhibition in RCC.…”

Section: Introductionmentioning

confidence: 99%

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

et al. 2013

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Since renal cell carcinoma (RCC) often presents asymptomatically, patients are commonly diagnosed at the metastatic stage when treatment options are limited and survival is poor. Given that progression-free survival with current therapies for metastatic RCC is only one to two years and existing drugs are associated with a high rate of resistance, new pharmacological targets are desperately needed. We identified and evaluated the nuclear exporter protein, chromosome region maintenance protein 1 (CRM1), as a novel potential therapeutic for RCC. Purpose To evaluate novel, selective inhibitors of nuclear export as potential RCC therapeutics. Materials and Methods Efficacy of the CRM1 inhibitors, KPT-185 and -251, was tested in several RCC cell lines and in a RCC xenograft model. Apoptosis and cell cycle arrest were quantified, and localization of p53 family proteins was assessed using standard techniques. Results KPT-185 attenuated CRM1 and showed increased cytotoxicity in RCC cells in vitro, with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused both p53 and p21 to remain primarily in the nucleus in all RCC cell lines, suggesting a mechanism of action of these compounds dependent upon tumor-suppressor protein localization. Furthermore, when administered orally in a high-grade RCC xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on-target effects and with no obvious toxicity. Conclusions The CRM1 inhibitor family of proteins are novel therapeutic targets RCC and deserve further intensive investigation in this and other urologic malignancies.

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p53-dependent anticancer effects of leptomycin B on lung adenocarcinoma

Abstract: Our results suggest that LMB has anti-cancer potential and provides a new regimen of individualized therapy for lung cancer treatment.

Cited by 38 publications

References 56 publications

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

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

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

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