Furthermore CRM is known to export primarily

Furthermore, CRM1 is known to export primarily p53+/+ from the nucleus to the cytoplasm of cancer VSV-G Peptide australia via its C-terminal NES, allowing for efficient degradation of p53 by the proteasome [9]. Also, researchers have reported that p53 was considered to be a critical mediator of CRM1 inhibitor-induced cell apoptosis [19], [25]. Interestingly, in this present study, we noticed that treatment with KPT-185 decreased the expression of mutant p53 in Mino, Jurkat, and RL cells lines but increased the expression of p53+/+ in Granta519 cells. Given the different functions of various p53 genotypes in tumor growth and survival, these results indicated that p53 may be a mediator of SINE-induced antitumor activity. Another CRM1-dependent process affected by treatment with KPT-185 was the reduction of NF-κB expression in Jeko-1, Hut102, Mino, RL, Jurkat and Hut78 cells. NF-κB plays important roles in various types of cancer cells and is an important target for anticancer therapy [35]. Therefore, downregulated expression of NF-κB may be a reasonable explanation for the antilymphoma activity of KPT-185. Notably, we made the novel observation that expression of the growth-promoting protein survivin was greatly downregulated in the cells with KPT-185 treatment. Furthermore, the enhanced nuclear staining of survivin in Jeko-1 tumor sections visualized by immunohistochemistry indicated that survivin was trapped within the nucleus by KPT-276 treatment. As an inhibitor member of the apoptosis protein family, survivin exhibits antiapoptotic characteristics. Authors have reported elevated survivin expression to confer radiation or drug resistance, whereas artificial knockdown of survivin expression increases the susceptibility of cells to apoptosis [36], [37], [38]. Furthermore, earlier studies have demonstrated that survivin is actively and rapidly exported into the cytoplasm, and it contains a canonical NES domain. Exclusion of survivin from the nucleus is mediated by the classic nuclear export mechanism involving the interaction between the transport receptor CRM1 and Ran-guanosine triphosphate [12], [39], [40]. Recent reports also demonstrated that preferentially cytoplasmic survivin is “cytoprotective” in tumor cells, whereas nuclear survivin may be indicative of “impaired survivin function.” [13], [14], [41] Therefore, patients with cancer having predominantly nuclear survivin in tumor cells may have reduced tumor-protective survivin activity, which may ultimately translate into a favorable prognosis. Therefore, targeting the survivin/CRM1 interface may be a powerful approach to NHL therapy. Our present results indicated an important antitumor mechanism of SINEs based on expression and cellular localization of survivin. 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.