As the main effector of nuclear cytoplasmic transport in cel

As the main effector of nuclear-cytoplasmic transport in cells, XPO1 also exports cargos such as tumor suppressor and growth regulatory proteins. Deregulation of the XPO1-mediated nuclear export can result in uncontrolled cell growth and carcinogenesis (Kau et al., 2004; Turner and Sullivan, 2008) and increased expression of XPO1 has been observed in several cancers (van der Watt et al., 2009; Yao et al., 2009; Huang et al., 2009; Noske et al., 2008). Several inhibitors of XPO1 exist among which leptomycin B is best known (Nishi et al., 1994; Wolff et al., 1997). Inhibition of XPO1 restores tumor suppressor function and induces cytotoxicity in cancer THZ1 Hydrochloride Supplier (Lain et al., 1999; Smart et al., 1999). Another XPO1 inhibitor CBS9106 showed anti-tumor activity in a variety of cancer cell lines and displayed tumor growth suppression in multiple myeloma xenograft (Sakakibara et al., 2011). However, the effect of XPO1 inhibition on PEL has not been studied. Recently selective inhibitors of the exportin-1 (XPO1) mediated nuclear export (SINE) were found to have great potential against various solid and hematological cancers in in vitro as well as in vivo models of NHL and other hematological malignancies (Etchin et al., 2013a,b; Inoue et al., 2013; Lapalombella et al., 2012; Tai et al., 2014; Zhang et al., 2013; Ranganathan et al., 2012; Kojima et al., 2013). SINE are orally bioavailable optimized analogues of the N-azolylacrylate small-molecule inhibitors affecting XPO1-mediated nuclear export (Van Neck et al., 2008; Daelemans et al., 2002). They selectively bind into the hydrophobic cargo-binding pocket of XPO1 and interact covalently with Cys528 of XPO1 through a Michael type addition (Etchin et al., 2013b; Lapalombella et al., 2012; Van Neck et al., 2008; Neggers et al., 2015). The lead SINE selinexor (KPT-330) is currently in different Phase 1 and 2 clinical studies for solid and hematological malignancies and early results show that selinexor is well tolerated with clear anti-tumor activity.
Materials and Methods
Results
Discussion Our results are in agreement with earlier studies in acute myeloid leukemia where p53 has been found a major determinant of XPO1-inhibition-induced apoptosis by KPT-185 (Kojima et al., 2013). In addition, in chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma XPO1 inhibition by SINE blocks NF-κB activity (Lapalombella et al., 2012; Etchin et al., 2013a,b) and down-regulates NF-κB target genes (Lapalombella et al., 2012) by increasing nuclear levels of IκB. NF-κB is implicated also in survival and drug resistance in multiple myeloma (Hideshima et al., 2007) and other tumors and SINE compounds have demonstrated promising activity in these resistant hematological malignancies. Moreover, studies in chronic lymphocytic leukemia and multiple myeloma demonstrated the inhibitory activity of KPT-185 on the production of the inflammatory cytokines such as IL-6 (Lapalombella et al., 2012), which is also important for the persistence of PEL (Jones et al., 1999). Several studies have revealed the tolerability profile of SINE in vivo (Etchin et al., 2013b; Lapalombella et al., 2012; Zhang et al., 2013; London et al., 2014). Most importantly, the clinical candidate SINE selinexor (KPT-330) is yet in several phase 1 and 2 trials in human for advanced malignancies (clinicaltrials.gov) and demonstrated high response rates as single agent in trials for heavily pretreated relapsed and refractory hematological and solid tumor malignancies (Kuruvilla et al., 2013; Chen et al., 2014). Importantly, the demonstrated in vivo efficacy of SINE against hematological tumors indicates that the drug is active in host cells and/or reservoirs of HIV. Although anti-HIV activity of SINE in animal models remains to be directly demonstrated, our in vitro results together with the demonstrated in vivo activity of SINE in hematological tumors provide strong evidence for in vivo anti-HIV effectiveness. Furthermore, SINE might have the potential of successfully targeting HIV persistence. In patients treated with combination antiretroviral therapy, infected cells can persist for a long time and are an important obstacle for curing HIV infection. Importantly it was recently demonstrated that in many cases these persistently infected cells expand from a single clone as a result of integration in genes involved in controlling cell growth and division which the survival and expansion of the infected cells (Maldarelli et al., 2014). Therefore, to successfully target HIV persistence with the aim of realizing a potential cure, it will be important to suppress both viral replication as well as to inhibit the expansion of infected cells.