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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 survivin [corrected] in prostate cancer models.

Gravina GL, Mancini A, Sanita P, Vitale F, Marampon F, Ventura L, Landesman Y, McCauley D, Kauffman M, Shacham S, Festuccia C - BMC Cancer (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy. giovanniluca.gravina@libero.it.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Dose-dependent effects of different KPT compounds in BPH-1, LnCaP (AR+/AD/p53wt), LAPC-4 (AR+/AD/p53mutant), 22rv1(AR+/AI/p53 wt) and PC3 (AR-/p53 ) cells treated with varying doses (0, 1, 10, 50, 100, 500 and 1000 nM) of different KPT compounds and assessed viability at 72 hours after treatment: KPT-127 (a), KPT-185 (b), KPT-207 (c), KPT-225 (d), KPT-251 (e) and KPT-330 (f). g IC50 for each compound was then calculated for the wide set of PCa cell lines
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Fig2: Dose-dependent effects of different KPT compounds in BPH-1, LnCaP (AR+/AD/p53wt), LAPC-4 (AR+/AD/p53mutant), 22rv1(AR+/AI/p53 wt) and PC3 (AR-/p53 ) cells treated with varying doses (0, 1, 10, 50, 100, 500 and 1000 nM) of different KPT compounds and assessed viability at 72 hours after treatment: KPT-127 (a), KPT-185 (b), KPT-207 (c), KPT-225 (d), KPT-251 (e) and KPT-330 (f). g IC50 for each compound was then calculated for the wide set of PCa cell lines

Mentions: Six SINE analogs KPT-127, KPT-185, KPT-205, KPT-227, KPT251 and KPT-330 sharing a trifluoromethyl phenyl triazole scaffold [51, 52], were investigated for their growth inhibitory and apoptotic potential in our PCa cell panel. Therefore, the effects of these XPO1 inhibitors were evaluated on the growth of PCa cell lines performing dose- and time-dependent studies. To examine the dose-dependent effects of these compounds, we treated cells with varying doses of the compounds (0, 1, 10, 50, 100, 500 and 1000 nM) and assessed viability at 72 hours after treatment. The IC50 for each compound was then calculated. In Fig. 2a-f we show the growth curves for LnCAP, LAPC-4, 22rv1 and PC3 cells, exposure to sub-micromolar concentrations of SINE for 72 hrs. In Fig. 2g, we summarized IC50 values calculated in our cell systems. Most significantly, at the concentrations tested, the SINE showed no effect on growth of normal or hyperplastic prostate epithelial cells (BPH-1, RWPE-1 and EPN). We observed that all SINE compounds show good activity in PCa cell lines with IC50 values in the range of 43 and 700 nM. KPT-330, currently in phase I clinical trials (ClinicalTrials.gov) and KPT-127 were the most potent growth inhibitors with IC50 between 43 and 201 nM, whereas the least activity was observed with KPT-251 (IC50 values ranged between 150 and 300 nM) and KPT-185 (IC50 values ranged between 180 and 700 nM). Statistical analyses showed a significant correlation between efficacy of SINE compounds and XPO-1 expression with higher XPO-1 protein levels being correlated with lower IC50 values (and thus with higher sensitivity). The better correlation was found for KPT-127 and KPT-207 (r = −0.728 and −0.717, P < 0.005), KPT-330 (r = −0.613, P < 0.01) and KPT-251 (r = −0.485, P < 0.05). The effects of SINE compounds were higher in CRPC when compared to androgen dependent prostate cancer cell lines. Therefore the molecular analysis and the in vivo studies were made in PC3, DU145 and 22rv1 CRPC models.Fig. 2


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

Gravina GL, Mancini A, Sanita P, Vitale F, Marampon F, Ventura L, Landesman Y, McCauley D, Kauffman M, Shacham S, Festuccia C - BMC Cancer (2015)

Dose-dependent effects of different KPT compounds in BPH-1, LnCaP (AR+/AD/p53wt), LAPC-4 (AR+/AD/p53mutant), 22rv1(AR+/AI/p53 wt) and PC3 (AR-/p53 ) cells treated with varying doses (0, 1, 10, 50, 100, 500 and 1000 nM) of different KPT compounds and assessed viability at 72 hours after treatment: KPT-127 (a), KPT-185 (b), KPT-207 (c), KPT-225 (d), KPT-251 (e) and KPT-330 (f). g IC50 for each compound was then calculated for the wide set of PCa cell lines
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666032&req=5

Fig2: Dose-dependent effects of different KPT compounds in BPH-1, LnCaP (AR+/AD/p53wt), LAPC-4 (AR+/AD/p53mutant), 22rv1(AR+/AI/p53 wt) and PC3 (AR-/p53 ) cells treated with varying doses (0, 1, 10, 50, 100, 500 and 1000 nM) of different KPT compounds and assessed viability at 72 hours after treatment: KPT-127 (a), KPT-185 (b), KPT-207 (c), KPT-225 (d), KPT-251 (e) and KPT-330 (f). g IC50 for each compound was then calculated for the wide set of PCa cell lines
Mentions: Six SINE analogs KPT-127, KPT-185, KPT-205, KPT-227, KPT251 and KPT-330 sharing a trifluoromethyl phenyl triazole scaffold [51, 52], were investigated for their growth inhibitory and apoptotic potential in our PCa cell panel. Therefore, the effects of these XPO1 inhibitors were evaluated on the growth of PCa cell lines performing dose- and time-dependent studies. To examine the dose-dependent effects of these compounds, we treated cells with varying doses of the compounds (0, 1, 10, 50, 100, 500 and 1000 nM) and assessed viability at 72 hours after treatment. The IC50 for each compound was then calculated. In Fig. 2a-f we show the growth curves for LnCAP, LAPC-4, 22rv1 and PC3 cells, exposure to sub-micromolar concentrations of SINE for 72 hrs. In Fig. 2g, we summarized IC50 values calculated in our cell systems. Most significantly, at the concentrations tested, the SINE showed no effect on growth of normal or hyperplastic prostate epithelial cells (BPH-1, RWPE-1 and EPN). We observed that all SINE compounds show good activity in PCa cell lines with IC50 values in the range of 43 and 700 nM. KPT-330, currently in phase I clinical trials (ClinicalTrials.gov) and KPT-127 were the most potent growth inhibitors with IC50 between 43 and 201 nM, whereas the least activity was observed with KPT-251 (IC50 values ranged between 150 and 300 nM) and KPT-185 (IC50 values ranged between 180 and 700 nM). Statistical analyses showed a significant correlation between efficacy of SINE compounds and XPO-1 expression with higher XPO-1 protein levels being correlated with lower IC50 values (and thus with higher sensitivity). The better correlation was found for KPT-127 and KPT-207 (r = −0.728 and −0.717, P < 0.005), KPT-330 (r = −0.613, P < 0.01) and KPT-251 (r = −0.485, P < 0.05). The effects of SINE compounds were higher in CRPC when compared to androgen dependent prostate cancer cell lines. Therefore the molecular analysis and the in vivo studies were made in PC3, DU145 and 22rv1 CRPC models.Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy. giovanniluca.gravina@libero.it.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus