Nuclear export inhibitors (NEIs) as novel cancer therapeutics

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 5609 CRM1 is an essential nuclear export protein responsible for shuttling a wide variety of important “cargo” proteins (e.g. p53, BCR-Abl, FOXO-3a) out of the nucleus and into the cytoplasm. Leptomycin B and its analogs are potent nuclear export inhibitors (NEIs) which derive their activity through the direct inhibition and covalent modification of CRM1. Analyses of the in vitro and in vivo activities of NEIs have revealed that CRM1 is a novel target for the treatment of cancer. NEIs cause the rapid nuclear accumulation of CRM1 cargo proteins in vitro . Nuclear export inhibition is rapidly observed (within 15 to 30 minutes) at drug concentrations as low as 10 nM, and the export blockade is long-lasting (greater than 24 hours). Activation of many CRM1 cargo proteins in the nucleus can lead to inhibition of proliferation, and treated cells arrest in the G1 phase of the cell cycle. Furthermore, exposure to NEIs also leads to an increase in multiple markers of apoptosis including plasma membrane alterations (Annexin V binding) and caspase activation. Comparisons of p53 wild-type and dominant negative pairs of tumor cell lines demonstrate that p53 wild-type cell lines are particularly sensitive to NEI-induced apoptosis. Induction of apoptosis is observed in tumor derived cell lines (e.g. SiHa, HCT-116 and LNCaP), but not normal cells (e.g. MRC5, WI-38, and IMR-90). NEIs show potent activity as single agents in multiple in vivo tumor models. Moreover, this mechanism may also have numerous applications in combination therapies, as NEIs are synergistic when combined with a broad spectrum of cancer therapeutics in in vitro experiments. Because of their novel mechanism of action, potent activity both in vitro and in in vivo tumor models, and promising application for combination therapies, NEIs have excellent potential as anti-cancer agents.