ArticleGastroenterology2013
Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.
Article in Gastroenterology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
80 citing papers in PubMed, 114 citations in OpenAlex.
- Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Trial
- Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma.BMC veterinary research · 2018Trial
- Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors.Journal of hematology & oncology · 2016Trial
- Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?Molecular biology reports · 2024Review
- The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells.Leukemia · 2024Article
- Article
- The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials.Clinical and translational medicine · 2024Review
- Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.Nature communications · 2024Article
- Article
- Selective nuclear export inhibitor KPT‑330 enhances the radiosensitivity of esophageal carcinoma cells.Experimental and therapeutic medicine · 2023Article
- Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling.International journal of molecular sciences · 2023Article
- Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.Nature biomedical engineering · 2022Article
- Selinexor and the Selective Inhibition of Nuclear Export: A New Perspective on the Treatment of Sarcomas and Other Solid and Non-Solid Tumors.Pharmaceutics · 2021Review
- The nuclear export protein XPO1 - from biology to targeted therapy.Nature reviews. Clinical oncology · 2021Review
- The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response.Frontiers in microbiology · 2021Article
- NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.Molecular cancer therapeutics · 2020Article
- Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.Journal of experimental & clinical cancer research : CR · 2020Review
- Transcriptome Profiling of Acquired Gefitinib Resistant Lung Cancer Cells Reveals Dramatically Changed Transcription Programs and New Treatment Targets.Frontiers in oncology · 2020Article
- Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.International journal of molecular sciences · 2019Article
- DNA-Methylation-Caused Downregulation ofCancers · 2019Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsTumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells.
methodsWe studied the effects of SINE analogs in a panel of pancreatic cancer cell lines and nontransformed human pancreatic ductal epithelial cells using proliferation, apoptosis, immunoblot, co-immunoprecipitation, small inhibitor RNA, and fluorescence microscopy analyses. The effects of the SINEs also were investigated in mice with subcutaneous and orthotopic tumors.
resultsSINEs (KPT-185, KPT-127, KPT-205, and KPT-227) inhibited proliferation and promoted apoptosis of pancreatic cancer cells, but did not affect human pancreatic ductal epithelial cells. The nuclei of cells incubated with KPT-185 accumulated tumor-suppressor proteins (p27, FOXO, p73, and prostate apoptosis response-4 [PAR-4]) and inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that bind to SINEs (Cys-528), or small inhibitor RNA knockdown of PAR-4, prevented the ability of KPT-185 to block proliferation and induce apoptosis of pancreatic cancer cells. Oral administration of KPT-330 to mice reduced growth of subcutaneous and orthotopic xenograft tumors without major toxicity. Analysis of tumor remnants showed that KPT-330 disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of tumor cells.
conclusionsWe identified SINEs that inhibit CRM-1 and promote nuclear accumulation of tumor-suppressor proteins in pancreatic cancer cells. Oral administration of the drug to mice reduces growth of xenograft tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.