page_title: Selective inhibitor of nuclear export
section_title: Mechanism of action
hierarchical_section_title: Selective inhibitor of nuclear export / Mechanism of action
caption_attribution_description: Українська: RanГТФ - транспортний цикл
context_page_description: Selective inhibitors of nuclear export are drugs that block exportin 1, a protein involved in transport from the cell nucleus to the cytoplasm. This causes cell cycle arrest and cell death by apoptosis. Thus, SINE compounds are of interest as anticancer drugs; several are in development, and one has been approved for treatment of multiple myeloma as a drug of last resort.
  The prototypical nuclear export inhibitor is leptomycin B, a natural product and secondary metabolite of Streptomyces bacteria. Although it is nonselective and too toxic for clinical use in humans, the discovery of its mechanism of action and antitumor properties prompted development of the SINE compounds.
context_section_description: SINEs work by binding to CRM1, a karyopherin which performs nuclear transport of hundreds of proteins—including tumor suppressors, oncogenes, and proteins involved in governing cell growth—from the cell nucleus to the cytoplasm. CRM1 it is often overexpressed and misregulated in cancer, and is the sole transporter of many proteins essential for cancer cell proliferation and spread. By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell growth, ultimately triggering apoptosis. In vitro, this effect appears to spare normal (non-malignant) cells. Nevertheless, because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which causes a high rate of adverse reactions.
caption: Schematic illustration of the Ran cycle of nuclear transport. SINE compounds inhibit this process at the nuclear export receptor (upper right).
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