Leptomycin B is the dominant member of the Leptomycin class, secondary metabolites isolated from selected Streptomyces strains. It is a bioactive small molecule with antifungal and antibacterial activity. It is a nuclear export inhibitor, targeting chromosome region maintenance 1 (CRM1), a nuclear export receptor and a protein in the nuclear export signal (NES) thus can be used as a tool to study nuclear export. Leptomycin B is an inhibitor of nucleo-cytoplasmic translocation of HIV-1 Rev protein and Rev-dependent mRNA. It has anti-cancer activity and can modulate cancer-specific pathways.
Leptomycin B is soluble in ethanol and methanol, practically insoluble in water, and unstable in DMSO.
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| Mechanism of Action |
Leptomycin B is a highly specific and potent inhibitor of CRM1 function. It binds irreversibly with the sulfhydryl group of a Cys residue in the cargo biding domaine of CRM1. It affects proteins c-Abl, cyclin B1, HIV-1 Rev, IκB, MPF, MAP/ERK, MDM2/p53, NF-κB/IκB7 and PKA. Leptomycin B inhibits the export of many RNAs (COX-2, cFOS mRNA). |
| Microbiology Applications | Leptomycin B is an inhibitor of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. The HIV-1 regulatory protein Rev is required for unspliced and incompletely spliced viral mRNAs to appear in the cytoplasm and thus for viral replication. |
| Cancer Applications | Leptomycin B can be used as an anti-tumor agent against murine experimental lung cancer tumors using human lung adenocarcinoma epithelial cell lines A549 and NCI-H358 when pretreated with doxorubicin. This was accomplished through activating and restoring p53 and potentially other signaling pathways involving sequestosome 1, showing that Leptomycin B can modulate cancer-specific pathways (Lu et al, 2012).
Leptomycin B inhibits COX-2 expression induced by serum withdrawal in a human breast cancer cell line MDA-MB-231. LMB may inhibit COX-2 expression by blocking nuclear export of COX-2 mRNA, which may be an important control point of COX-2 gene expression (Jang et al, 2003). |
| References |
Hamamoto T et al (1983) Leptomycins A and B, new antifungal antibiotics. I. Taxonomy of the producing strain and their fermentation, purification and characterization.. J Antibiot. 36:639 Lu C, Shao C, Cobos E, Singh KP, and Gao W (2012) Chemotherapeutic sensitization of Leptomycin B resistant lung cancer cells by pretreatment with doxorubicin. PLoS One. 7(3):e32895 PMID 22412944 Wang Y et al (2004) Novel leptomycins from a Streptomyces strain A92-308902: Inhibitors of the nucleo-cytoplasmic translocation of the HIV-1 regulatory protein Rev. Helvetica 80(7):2157-2167 |
