Renal cell carcinoma often presents asymptomatically and patients are commonly diagnosed at the metastatic stage, when treatment options are limited and survival is poor. Since progression-free survival using current therapy for metastatic renal cell carcinoma is only 1 to 2 years and existing drugs are associated with a high resistance rate, new pharmacological targets are needed. We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma.
Materials and methods:
We tested the efficacy of the CRM1 inhibitors KPT-185 and 251 in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model. Apoptosis and cell cycle arrest were quantified and localization of p53 family proteins was assessed using standard techniques.
KPT-185 attenuated CRM1 and showed increased cytotoxicity in renal cell carcinoma cells in vitro with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused p53 and p21 to remain primarily in the nucleus in all renal cell carcinoma cell lines, suggesting that the mechanism of action of these compounds depends on tumor suppressor protein localization. Furthermore, when administered orally in a high grade renal cell carcinoma xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on target effects and no obvious toxicity.
The CRM1 inhibitor protein family is a novel therapeutic target for renal cell carcinoma that deserves further intensive investigation for this and other urological malignancies.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Infection with human immunodeficiency virus (HIV) compromises the body's immune system leaving infected individuals vulnerable to other pathologies including cancer. Some forms of cancer typically develop in AIDS patients, as for example the very aggressive and most often deadly primary effusion lymphoma (PEL). There is currently no standard treatment for PEL but the use of anti-HIV drugs is associated with better prognosis. Here we show in preclinical tests that inhibitors of nuclear export suppress both HIV replication as well as PEL progression. These findings provide a rationale for further evaluating these inhibitors as treatment strategy for dual HIV/lymphoma therapy.
"The CRM1 inhibitors KPT-185 and KPT-251 were tested in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model (i.e., Caki-1 cells were transplanted subcutaneously into athytic Nu/Nu mice). Compared to sorafenib, the SINE compounds exhibited better tumor growth inhibition and apparent sequestration of p53 and p21 in the nucleus, as well as a decrease in CRM1 protein expression, in vitro and in vivo (Inoue et al., 2013). "
"Recently, novel, orally bioavailable, small molecule, drug-like, selective inhibitors of XPO1 mediated nuclear (SINE) have been described . SINE compounds bind irreversibly to the Cys528 NES recognizing residue in XPO1 and block its ability to bind to cargo proteins . SINE have been shown to potently inhibit the growth of multiple cancer cell lines and animal tumor models such as acute myeloid leukemia , mantle cell lymphoma , and other hematological malignancies . "
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