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  • Since we found that the pharmacokinetic

    2019-08-13

    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.
    Role of funding source
    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 Carfilzomib msds 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.