Since we found that the

Since we found that the pharmacokinetic properties of KPT-185 were unsuitable when given subcutaneously or orally, it is not a candidate for in vivo therapy for NHL. However, the pharmacokinetic properties of KPT-276, a CRM1-inhibiting SINE structurally related to and with functional activities similar to those of KPT-185 in vitro, are suitable for oral administration. In the present study, KPT-276 administered orally at 100mg/kg three times a week was well tolerated and exhibited a high level of antitumor activity in an NHL xenograft mouse model. These results indicate that KPT-276 is a novel CRM1 inhibitor and a promising candidate for the treatment of NHL.
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Conflict of interest statement
Acknowledgments
Contributors. YK S and XH H provided the conception and design of this study; all authors performed the acquisition, analysis and interpretation of data; YK S, XH H and JF W wrote the draft; all authors participated in revising and approving submit of the manuscript; XH H and JF W contributed equally to this work.
Introduction Inflammatory bowel disease (IBD) is a chronic and non-specific inflammatory disease that primarily comprises Crohn's disease (CD) and ulcerative colitis (UC). CD is a chronic relapsing systemic inflammatory disease that may affect any part of the gastrointestinal tract from the 4SC-202 australia to the anus, but especially the distal part of the small intestine (terminal ileitis) and the colon; CD is characterized by bloody diarrhea, abdominal pain, weight loss, and increased risk of gastrointestinal malignancy [1]. Various epidemiological studies have reported that CD is most prevalent in Western industrialized countries [2], [3], although the incidence of CD has recently increased in China [4]. Treatment of CD remains a major challenge for clinicians, as no curative therapy currently exists. Thus, marked attention has been paid to the development of new treatments for CD [5]. Although the etiology of CD remains unknown, evidence suggests that genetic, immunological, and environmental factors play roles in the pathogenesis of CD and that intestinal barriers are primary contributing factors [6]. Intestinal epithelial cells (IECs) cover the entire length of the gastrointestinal tract, forming a primary barrier that protects the mucosal surface from harmful molecules and bacteria, and contribute to the regulation of intestinal immune responses [7]. It is known that the balance between epithelial cell apoptosis and proliferation is pivotal for the maintenance of mucosal integrity in the intestine [8]. In CD patients, increased IEC apoptosis has been detected at acute inflammatory sites [9]. However, the mechanisms that contribute to IEC apoptosis in CD remain unknown. Chromosome region maintenance-1 (CRM1) is the only nuclear exporter protein in the karyopherin-β protein family that contributes to the trafficking of numerous proteins, including tumor suppressor, growth regulator/pro-inflammatory and anti-apoptotic proteins, and RNAs essential for ribosomal biogenesis from the nucleus [10], [11], [12], [13], [14]. CRM1 recognizes the leucine-rich nuclear export signal (NES) of cargo proteins that must be shuttled out of the nucleus and then transports them to the cytoplasm [15]. Because nucleocytoplasmic trafficking of proteins/RNAs is essential for normal cellular function, CRM1 has been reported to play crucial roles in the cell cycle, mitosis and replication. Moreover, CRM1 is up-regulated in a variety of solid tumor types, such as gliomas and pancreatic, cervical, and hematological malignancies [16], [17], [18]. In fact, abnormally high CRM1 expression is correlated with poor patient prognosis in these malignancies. Therefore, therapeutic targeting CRM1 has emerged as a novel cancer treatment strategy. As reported, CRM1 inhibition can trigger human melanoma cell apoptosis by perturbing multiple cellular pathways [19]. On the other hand, CRM1 has been reported to regulate neuronal apoptosis after traumatic brain injury in adult rats [20]. Therefore, CRM1 is a multifunctional protein, but its expression and potential functions have not been well elucidated in CD.