CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo

Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. CRM1 (chromosome maintenance protein-1) is a ubiquitous protein that exports large proteins (>40 kDa) from the nucleus to the cytoplasm. We found that small-molecule Selective Inhibitors of Nuclear Export (SINE) prevent CRM1-mediated export of p53 and topoisomerase IIα (topo IIα). SINE's CRM1-inhibiting activity was verified by nuclear-cytoplasmic fractionation and immunocytochemical staining of the CRM1 cargoes p53 and topo IIα in MM cells. We found that SINE molecules reduced cell viability and induced apoptosis when used as both single agents in the sub-micromolar range and when combined with doxorubicin, bortezomib, or carfilzomib but not lenalidomide, melphalan, or dexamethasone. In addition, CRM1 inhibition sensitized MM cell lines and patient myeloma cells to doxorubicin, bortezomib, and carfilzomib but did not affect peripheral blood mononuclear or non-myeloma bone marrow mononuclear cells as shown by cell viability and apoptosis assay. Drug resistance induced by co-culture of myeloma cells with bone marrow stroma cells was circumvented by the addition of SINE molecules. These results support the continued development of SINE for patients with MM.

• Publication year

  2013

• Venue

  Journal of Cancer

• Publication date

  2013-09-10

• Fields of study

  Medicine

• Identifiers
  DOI 10.7150/jca.7080PMID 24155773PMCID 3805989
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2013cited by this paper
• Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.

  2013cited by this paper
• CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth.

  2013cited by this paper
• Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells

  2012cited by this paper
• Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.

  2012cited by this paper
• Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia.

  2012cited by this paper
• Combination of HDAC and topoisomerase inhibitors in small cell lung cancer

  2012cited by this paper
• Nuclear export of proteins and drug resistance in cancer.

  2012cited by this paper
• Acquisition of Resistance toward HYD1 Correlates with a Reduction in Cleaved α4 Integrin Expression and a Compromised CAM-DR Phenotype

  2011cited by this paper
• CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity.

  2011cited by this paper
• Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition.

  2009cited by this paper
• New Rev-export inhibitor from Alpinia galanga and structure-activity relationship.

  2009cited by this paper
• Identification of nuclear export inhibitors with potent anticancer activity in vivo.

  2009cited by this paper
• HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells

  2009cited by this paper
• CRM1-mediated nuclear export of proteins and drug resistance in cancer.

  2008cited by this paper
• Nucleocytoplasmic Shuttling of the Retinoblastoma Tumor Suppressor Protein via Cdk Phosphorylation-dependent Nuclear Export*

  2006cited by this paper
• An intron with a constitutive transport element is retained in a Tap messenger RNA

  2006cited by this paper
• Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia

  2005cited by this paper
• Cytoplasmic Mislocalization of p27Kip1 Protein Is Associated with Constitutive Phosphorylation of Akt or Protein Kinase B and Poor Prognosis in Acute Myelogenous Leukemia

  2004cited by this paper
• The cytoplasmic trafficking of DNA topoisomerase IIalpha correlates with etoposide resistance in human myeloma cells.

  2004cited by this paper
• Human topoisomerase IIα nuclear export is mediated by two CRM-1-dependent nuclear export signals

  2004cited by this paper
• Ratjadone and leptomycin B block CRM1‐dependent nuclear export by identical mechanisms

  2004cited by this paper
• A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells.

  2003cited by this paper
• Multi parameter in vitro testing of ratjadone using flow cytometry

  2003cited by this paper
• Nuclear export of the APC tumour suppressor controls β‐catenin function in transcription

  2003cited by this paper
• The importance of p53 location: nuclear or cytoplasmic zip code?

  2003cited by this paper
• Bcr‐Abl upregulates cytosolic p21WAF‐1/CIP‐1 by a phosphoinositide‐3‐kinase (PI3K)‐independent pathway

  2003cited by this paper
• Ratjadones inhibit nuclear export by blocking CRM1/exportin 1.

  2003cited by this paper
• New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix.

  2002cited by this paper
• The Chemistry and Biology of Ratjadone

  2001cited by this paper
• Cell density‐dependent VP‐16 sensitivity of leukaemic cells is accompanied by the translocation of topoisomerase IIα from the nucleus to the cytoplasm

  2000cited by this paper
• Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region.

  1999cited by this paper
• Proliferation-associated nuclear antigen Ki-S1 is identical with topoisomerase II alpha. Delineation of a carboxy-terminal epitope with peptide antibodies.

  1995cited by this paper
• Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes.

  1995cited by this paper
• Purification and characterization of an altered topoisomerase II from a drug-resistant Chinese hamster ovary cell line.

  1989cited by this paper
• Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

  1984influential reference

• Selinexor’s Immunomodulatory Impact in Advancing Multiple Myeloma Treatment

  2025cites this paper
• Selinexor in acute myeloid leukemia: therapeutic applications and current challenges

  2025cites this paper
• Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma

  2025cites this paper
• Combination effect of Exportin 1 inhibitor (KPT-335) with doxorubicin or vincristine in canine lymphoma cell lines.

  2025cites this paper
• Impact of prior treatment on selinexor, bortezomib, dexamethasone outcomes in patients with relapsed/refractory multiple myeloma: Extended follow‐up subgroup analysis of the BOSTON trial

  2024cites this paper
• Unraveling the complexity of drug resistance mechanisms to SINE, T cell-engaging therapies and CELMoDs in multiple myeloma: a comprehensive review

  2024cites this paper
• 4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1

  2023cites this paper
• Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm.

  2023cites this paper
• Trifluoperazine Synergistically Potentiates Bortezomib-Induced Anti-Cancer Effect in Multiple Myeloma via Inhibiting P38 MAPK/NUPR1.

  2022cites this paper
• Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance

  2022cites this paper
• The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

  2022cites this paper
• Phase-separated nuclear bodies of nucleoporin fusions, SET-NUP214 and NUP98-HOXA9, promote condensation of MLL1 and CRM1 to activate target genes

  2022cites this paper
• Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes.

  2021cites this paper
• Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status

  2021cites this paper
• The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

  2021cites this paper
• Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials

  2021cites this paper
• Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

  2021cites this paper
• Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

  2020cites this paper
• Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements

  2020cites this paper
• Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma

  2020cites this paper
• Targeting nuclear import and export in hematological malignancies

  2020cites this paper
• Selinexor, Bortezomib, and Dexamethasone for Heavily Pretreated Multiple Myeloma: A Case Series.

  2020cites this paper
• NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors

  2020cites this paper
• Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer

  2020cites this paper
• Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma

  2020cites this paper
• The nuclear export protein XPO1 — from biology to targeted therapy

  2020cites this paper
• Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells

  2019cites this paper
• Updates and rationale of clinical trials in multiple myeloma

  2019cites this paper
• Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia

  2019cites this paper
• The Use of Murine Models for Studying Mechanistic Insights of Genomic Instability in Multiple Myeloma

  2019cites this paper
• Selective Inhibitors of Nuclear Export in the Treatment of Hematologic Malignancies.

  2019cites this paper
• Proteomics of nucleocytoplasmic partitioning.

  2019cites this paper
• Nucleocytoplasmic Shuttling of STATs. A Target for Intervention?

  2019cites this paper
• SWATH-MS based quantitative proteomics analysis reveals that curcumin alters the metabolic enzyme profile of CML cells by affecting the activity of miR-22/IPO7/HIF-1α axis

  2018cites this paper
• Clinical Implications of Targeting XPO1‐mediated Nuclear Export in Multiple Myeloma

  2018cites this paper
• Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents

  2018cites this paper
• Novel combination of tanshinone I and lenalidomide induces chemo-sensitivity in myeloma cells by modulating telomerase activity and expression of shelterin complex and its associated molecules

  2018cites this paper
• Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

  2018cites this paper
• Gambogenic acid synergistically potentiates bortezomib-induced apoptosis in multiple myeloma

  2017cites this paper
• Inhibitors and Poisons of Mammalian Type II Topoisomerases

  2017cites this paper
• Targeting Intrinsic and Extrinsic Vulnerabilities for the Treatment of Multiple Myeloma

  2017cites this paper
• Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

  2017cites this paper
• Investigating a novel small molecule inhibitor of nuclear import as an anti-cancer approach

  2016cites this paper
• XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma

  2016cites this paper
• Treatment of Relapsed/Refractory Multiple Myeloma.

  2016cites this paper
• Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

  2016cites this paper
• Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors

  2016influential citation
• With or Without You: Studying the Requirement of p53 for Anti-Cancer Responses to Nuclear Export Inhibitors

  2016cites this paper
• Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death

  2016cites this paper
• XPO1 Inhibition using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia by Targeting DNA Repair and Restoring Topoisomerase IIα to the Nucleus

  2016cites this paper
• Caractérisation d'anomalies cytogénétiques et moléculaires dans la leucémie lymphoïde chronique

  2015cites this paper
• KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models

  2015cites this paper
• Novel therapeutic targets in multiple myeloma.

  2015cites this paper
• XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

  2015cites this paper
• Structural Basis of Targeting the Exportin CRM1 in Cancer

  2015cites this paper
• The Nuclear Proteome of a Vertebrate.

  2015cites this paper
• Longitudinal tracking of single live cancer cells to understand cell cycle effects of the nuclear export inhibitor, selinexor

  2015cites this paper
• Protein profiling of mefloquine resistant Plasmodium falciparum using mass spectrometry-based proteomics

  2015cites this paper
• Clinical translation of nuclear export inhibitors in cancer.

  2014cites this paper
• Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents.

  2014cites this paper
• Nucleo-cytoplasmic transport as a therapeutic target of cancer

  2014cites this paper
• Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor

  2014cites this paper
• Nuclear trafficking in health and disease.

  2014cites this paper
• Atomic basis of CRM1-cargo recognition, release and inhibition.

  2014cites this paper
• CBS9106-Induced CRM1 Degradation Is Mediated by Cullin Ring Ligase Activity and the Neddylation Pathway

  2014cites this paper
• Structure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands

  2014cites this paper
• Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition?

  2014cites this paper