KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and surviving in prostate cancer models

BMC Cancer, Dec 2015

Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.

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KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and surviving in prostate cancer models

Gravina et al. BMC Cancer KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models Giovanni Luca Gravina 0 3 Andrea Mancini 0 3 Patrizia Sanita 0 3 Flora Vitale 0 3 Francesco Marampon 0 3 Luca Ventura 2 Yosef Landesman 1 Dilara McCauley 1 Michael Kauffman 1 Sharon Shacham 1 Claudio Festuccia 0 3 0 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila , L'Aquila , Italy 1 Karyopharm Therapeutics , Newton, MA , USA 2 Pathology Division, San Salvatore Hospital , L'Aquila , Italy 3 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila , L'Aquila , Italy Background and aims: Increased expression of Chromosome Region Maintenance (CRM-1)/exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods: We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions: XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation. Prostate cancer; Cyclin D1; Tumor suppressor proteins; CRM-1; XPO-1; KPT-330; Selinexor; Selective Inhibitors of Nuclear Export (SINE) Background Prostate cancer (PCa) is the second leading cause of cancer mortality in males >40 years of age in the USA and the third most common cause of cancer-related mortality in males [ 1 ]. PCa is generally a slow developing cancer, and 5- and 10-year relative survival rates of early stage PCa are 99 and 95 %, respectively [ 2 ]. Although hormone therapy is initially very effective, almost all tumors relapse to a hormone refractory stage. In the past, it was presumed that the expression of the androgen receptor (AR) is lost in the cells of advanced, hormonerefractory tumors but AR is rarely lost in human PCa specimens in vivo, even in those of CRPC [ 3 ]. Not only that AR is not lost, but it is transcriptionally active in the majority of recurrent CRPC [ 4 ]. There is experimental evidence that the Akt, mTOR and glycogen synthase kinase-3 (GSK-3β) pathways are involved in AR signaling [ 5, 6 ]. GSK-3β binds to the AR, forming a complex in the cytoplasm that are then imported into the nucleus upon androgenic stimulation. Inhibition of GSK-3β by activation of Akt/mTOR pathways results in increased nuclear export of AR and this export can be abrogated by the inhibition of XPO-1. GSK-3β/XPO-1 activity also regulates the levels of several nuclear and cytoplasmic proteins including survivin [ 7, 8 ] and cyclin D1 [ 8 ], which modulate cell division and apoptosis. Advanced castration resistant prostate cancer (CRPC) tumors are characterized by the activation of PI3K/AKT [ 9, 10 ]. One of the major effects of the activation of this pathway is XPO-1 dependent nuclear export of the tumor suppressor protein (TSP) FOXO into the nucleus, thus abolishing its activity [11]. Normally, low levels of FOXO protein are found in the cytoplasm. Shortly after SINE treatment, FOXO begins to accumulate in the nucleus where it binds to DNA and induces gene transcription that results in cancer cell death [ 12, 13 ]. Cancer cells utilize nuclear-cytoplasmic transport through the nuclear pore complex to effectively evade apopt (...truncated)


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Giovanni Gravina, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Dilara McCauley, Michael Kauffman, Sharon Shacham, Claudio Festuccia. KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and surviving in prostate cancer models, BMC Cancer, 2015, pp. 941, 15, DOI: 10.1186/s12885-015-1936-z