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Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo
- Source :
- Cancer Research. 69:510-517
- Publication Year :
- 2009
- Publisher :
- American Association for Cancer Research (AACR), 2009.
-
Abstract
- The export protein CRM1 is required for the nuclear export of a wide variety of cancer-related “cargo” proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency but limited in vivo efficacy due to toxicity. We now report a series of semisynthetic LMB derivatives showing substantially improved therapeutic windows. Exposure of cancer cells to these compounds leads to a rapid and prolonged block of nuclear export and apoptosis. In contrast to what is observed in cancer cells, these agents induce cell cycle arrest, but not apoptosis, in normal lung fibroblasts. These new nuclear export inhibitors (NEI) maintain the high potency of LMB, are up to 16-fold better tolerated than LMB in vivo, and show significant efficacy in multiple mouse xenograft models. These NEIs show the potential of CRM1 inhibitors as novel and potent anticancer agents. [Cancer Res 2009;69(2):510–7]
- Subjects :
- Cancer Research
Active Transport, Cell Nucleus
Mice, Nude
Receptors, Cytoplasmic and Nuclear
Apoptosis
Bone Neoplasms
Karyopherins
Biology
Article
Mice
XPO1
In vivo
Cell Line, Tumor
Animals
Humans
Nuclear export signal
Lung
Cell Nucleus
Osteosarcoma
Antibiotics, Antineoplastic
Cell Cycle
Fibroblasts
Cell cycle
HCT116 Cells
Xenograft Model Antitumor Assays
In vitro
Mice, Inbred C57BL
Oncology
Biochemistry
Cell culture
Cancer cell
Fatty Acids, Unsaturated
Cancer research
Female
Tumor Suppressor Protein p53
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 69
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....48e22cfd67e6a468252c14bd955a2a29