Abstract
Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I–III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.
Highlights
Nuclear export, mainly mediated by the nuclear export factor exportin-1, is an essential function in all eukaryote that transport nuclear export signal (NES) containing cargoes from the nucleus to the cytoplasm.[1]
We first present the background of nuclear–cytoplasmic transport, the nuclear export factor chromosomal region maintenance 1 (CRM1) and the cancer hallmark pathways affected by CRM1 inhibition
We discuss the details of leptomycin B (LMB) and SINE, with both being covalent CRM1 inhibitors
Summary
Qingxiang Sun[1,2], Xueqin Chen[2], Qiao Zhou[2], Ezra Burstein[3,4], Shengyong Yang[1] and Da Jia[1,5]. Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I–III) on both advanced-stage solid and hematological tumors. We compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy. Signal Transduction and Targeted Therapy (2016) 1, 16010; doi:10.1038/sigtrans.2016.10; published online 1 July 2016
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