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  • Although the phase I clinical trial of LMB was unsuccessful

    2021-04-07

    Although the phase I clinical trial of LMB was unsuccessful, the detailed review of this trial only mentions some malaise and anorexia as side effects, which are common for most effective chemotherapeutic drugs. These side effects may diminish if lower doses are administered. In view of the novel CRM1 inhibitors now being developed by different pharmaceutical companies,,48, 49, 50 we believe that the clinical usage of LMB deserves a thorough re-evaluation, especially in combination with other chemotherapeutic drugs at a low and nontoxic dose. Our recent studies have suggested that abrogation of CRM1 through LMB could inhibit lung cancer cell growth and induce cytotoxicity in lung cancer cells, with minimal effects on normal bronchial epithelial cells, and the combined therapy using initial doxorubicin treatment and subsequent LMB treatment could improve the effectiveness of therapeutic strategy for lung cancer treatment. The selective and potent antitumor cytotoxicity was further confirmed by the silencing of CRM1 using siRNA (data not shown). The finding from our in vivo xenograft nude mouse model in this study first demonstrated that CRM1 knockdown diminishes the tumorigenicity of lung cancer cells. In addition, the implementation of a very small and nontoxic dose of LMB could boost the efficacy of cisplatin. This combinative chemotherapy showed no additional side effects. Therefore, adding LMB to the treatment protocol could be another effective and clinically practical strategy to not only reduce the drug side effects but also enhance their efficacy, especially in advanced lung cancer, which is characterized by tumor chemoresistance.
    Introduction Crm1 (the Chromosome region maintenance 1 protein or Exportin 1) is a member of the Karyopherin β protein family and the major nuclear export receptor in the cell [1]. It mediates the nuclear export of cargo Tubastatin A and certain RNAs from the nucleus into the cytoplasm, across the nuclear pore complex (NPC), and thus facilitates protein and RNA subcellular localisation. Crm1 recognises cargo proteins that carry a nuclear export signal (NES) [2], typically containing three to four critically spaced leucines (LX(1–3)LX(2–3)LXJ, L: leucine, X: spacer, J: leucine, valine or isoleucine) [3], [4]. Such cargo proteins include various transcription factors [5], cell cycle proteins [6], [7], and signalling proteins [8], which require timely translocation across Tubastatin A the nuclear envelope. Many of the integral processes in the cell thus rely on Crm1 expression and function [9]. Recent studies have reported that the expression of Crm1 is altered in cancer. Crm1 protein levels are elevated in cervical cancer [10], ovarian cancer [11], osteosarcoma [12], glioma [13] and pancreatic cancer [14], with high levels of Crm1 being found to associate with poor patient survival [11], [12], [13], [14]. Moreover, Crm1 expression has been found to be elevated in transformed fibroblasts compared to normal fibroblasts, suggesting that the increased expression of Crm1 is a general feature of the transformed phenotype [10]. The high expression of Crm1 in cancer and transformed cells is functionally relevant, as the inhibition of its expression results in cell death via apoptosis, while inhibition of its expression in normal cells does not [10]. This implicates Crm1 as a potential anti-cancer drug target, and currently studies are underway aiming to develop effective inhibitors of Crm1 [15]. The increased expression of Crm1 protein in cancer derives from increased transcription of Crm1 mRNA [10], suggesting that a transcriptional regulatory mechanism exists for differential Crm1 expression in normal and cancer cells, possibly at the level of promoter control. However, little is known about the factors that regulate the Crm1 promoter. The aim of this study was therefore to investigate Crm1 promoter activity and to identify cis- and trans-elements necessary for high Crm1 expression in cancer cells. We report that NFY/CBP, Sp1 and p53 transcription factors bind the Crm1 promoter and play an important role in Crm1 promoter regulation in cancer and transformed cells.