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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

a CRM1 expression in normal prostate gland and BPH (a-c) and PCa of various Gleason score (d-g) and metastases (h, i). Prostate gland and BPH1 areas expressed very low levels of XPO-1/CRM1 or were negative whereas prostate cancer areas showed different CRM1 expression both in the cytoplasm and nuclei. Metastatic lesions showed very high stains mainly in the nucleus. b, c statistical evaluation of total (Global immunoreactivity score), nuclear and cytoplasm XPO-1 expression as indicated in material and methods. d Western blot analyses and densitometric values (arbitrary/normalized densitometric values, e for XPO-1 expression in some PCa and non neoplastic epithelial cells. f Comparison between XPO-1 in AR positive (LAPC-4, CWR22, LnCaP, LnCaP-104S, LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, DuCaP, VCaP, PC3AR and DU145AR) versus AR negative (PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cells lines. g Comparison between androgen-dependent (LAPC-4, CWR22, LnCaP, LnCaP-104S, DuCaP, VCaP, PC3AR and DU145AR) versus androgen independent/CRPC (LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cell lines
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Fig1: a CRM1 expression in normal prostate gland and BPH (a-c) and PCa of various Gleason score (d-g) and metastases (h, i). Prostate gland and BPH1 areas expressed very low levels of XPO-1/CRM1 or were negative whereas prostate cancer areas showed different CRM1 expression both in the cytoplasm and nuclei. Metastatic lesions showed very high stains mainly in the nucleus. b, c statistical evaluation of total (Global immunoreactivity score), nuclear and cytoplasm XPO-1 expression as indicated in material and methods. d Western blot analyses and densitometric values (arbitrary/normalized densitometric values, e for XPO-1 expression in some PCa and non neoplastic epithelial cells. f Comparison between XPO-1 in AR positive (LAPC-4, CWR22, LnCaP, LnCaP-104S, LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, DuCaP, VCaP, PC3AR and DU145AR) versus AR negative (PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cells lines. g Comparison between androgen-dependent (LAPC-4, CWR22, LnCaP, LnCaP-104S, DuCaP, VCaP, PC3AR and DU145AR) versus androgen independent/CRPC (LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cell lines

Mentions: Prostate tumors were grouped according to the Gleason score and staging. Bone metastases were also considered. In Fig. 1a, we show examples for XPO-1 expression in normal prostate gland, BPH (a-c), PCa of various Gleason score (d-g) and bone metastases (h-i). Immunoreactivity was scored as indicated in the materials and methods section. We observed that the global XPO-1 immune-reactivity scoring (GIRS) was significantly higher in PCa (8.35 ± 5.85; cases n = 99) when compared to benign hypertrophy (BPH; 5.25 ± 1.15; cases n = 38) with p < 0.001 as indicated in Fig. 1b. GIRS values were higher in Gleason scores > 7 when compared to Gleason scores ≤ 7 both when we considered GIR scores (11.23 ± 5.19 vs 7.47 ± 6.52, P < 0.001) as indicated in Fig. 1c and the percentage of patients having high GIR scores (>8) was 36/49 (73.9 %) vs 19/50 (38 %). No differences were observed in primary tumors from patients with metastatic or non metastatic tumors. Analyzing the nuclear and cytoplasm expression levels, we observed a significant increase in XPO-1 expression in the nucleus in cancer (3.24 ± 3.22) and BPH (1.33 ± 0.83) with p < 0.01 (Fig. 1b) and in Gleason scores > 7 when compared to Gleason scores ≤ 7 (5.27 ± 3.24 vs 2.88 ± 3.31, p < 0.001) and 30/49 [61.2 %] vs 16/50 [32 %] cases with high IRS (P < 0.001, Fig. 1c). The analysis performed on cytoplasm revealed differences between BPH (3.45 ± 1.07) and PCa (5.61 ± 3.22, P < 0.001, Fig. 1b) but no significant differences between values of IRS measured for Gleason scores >7 (5.91 ± 3.20) and ≤ 7 (4.88 ± 3.70, P = 0.086) or the percentage of cases with high IRS [36/49 (73.5 %) vs 28/50 (56 %)] as shown in Fig. 1c. Although the mean GIRS values showed no significant differences, the percentage of cases with high XPO-1 expression was significantly higher in primary tissues derived from metastatic compared to those observed in non metastatic cases. No statistical difference was observed in the comparisons with pathologic stage for nuclear or cytoplasm IR values. Nevertheless all metastatic lesions presented elevated GIRS and nuclear IRS for XPO-1.Fig. 1


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)

a CRM1 expression in normal prostate gland and BPH (a-c) and PCa of various Gleason score (d-g) and metastases (h, i). Prostate gland and BPH1 areas expressed very low levels of XPO-1/CRM1 or were negative whereas prostate cancer areas showed different CRM1 expression both in the cytoplasm and nuclei. Metastatic lesions showed very high stains mainly in the nucleus. b, c statistical evaluation of total (Global immunoreactivity score), nuclear and cytoplasm XPO-1 expression as indicated in material and methods. d Western blot analyses and densitometric values (arbitrary/normalized densitometric values, e for XPO-1 expression in some PCa and non neoplastic epithelial cells. f Comparison between XPO-1 in AR positive (LAPC-4, CWR22, LnCaP, LnCaP-104S, LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, DuCaP, VCaP, PC3AR and DU145AR) versus AR negative (PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cells lines. g Comparison between androgen-dependent (LAPC-4, CWR22, LnCaP, LnCaP-104S, DuCaP, VCaP, PC3AR and DU145AR) versus androgen independent/CRPC (LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cell lines
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Related In: Results  -  Collection

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Fig1: a CRM1 expression in normal prostate gland and BPH (a-c) and PCa of various Gleason score (d-g) and metastases (h, i). Prostate gland and BPH1 areas expressed very low levels of XPO-1/CRM1 or were negative whereas prostate cancer areas showed different CRM1 expression both in the cytoplasm and nuclei. Metastatic lesions showed very high stains mainly in the nucleus. b, c statistical evaluation of total (Global immunoreactivity score), nuclear and cytoplasm XPO-1 expression as indicated in material and methods. d Western blot analyses and densitometric values (arbitrary/normalized densitometric values, e for XPO-1 expression in some PCa and non neoplastic epithelial cells. f Comparison between XPO-1 in AR positive (LAPC-4, CWR22, LnCaP, LnCaP-104S, LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, DuCaP, VCaP, PC3AR and DU145AR) versus AR negative (PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cells lines. g Comparison between androgen-dependent (LAPC-4, CWR22, LnCaP, LnCaP-104S, DuCaP, VCaP, PC3AR and DU145AR) versus androgen independent/CRPC (LnCaP-104R1, LnCaP-C81, C4-2B, 22rv1, PC3 and PC3 variants [PC3PTEN, PC3M-pro4, PC3M-Ln4, PC3Me, PCb2] and DU145) PCa cell lines
Mentions: Prostate tumors were grouped according to the Gleason score and staging. Bone metastases were also considered. In Fig. 1a, we show examples for XPO-1 expression in normal prostate gland, BPH (a-c), PCa of various Gleason score (d-g) and bone metastases (h-i). Immunoreactivity was scored as indicated in the materials and methods section. We observed that the global XPO-1 immune-reactivity scoring (GIRS) was significantly higher in PCa (8.35 ± 5.85; cases n = 99) when compared to benign hypertrophy (BPH; 5.25 ± 1.15; cases n = 38) with p < 0.001 as indicated in Fig. 1b. GIRS values were higher in Gleason scores > 7 when compared to Gleason scores ≤ 7 both when we considered GIR scores (11.23 ± 5.19 vs 7.47 ± 6.52, P < 0.001) as indicated in Fig. 1c and the percentage of patients having high GIR scores (>8) was 36/49 (73.9 %) vs 19/50 (38 %). No differences were observed in primary tumors from patients with metastatic or non metastatic tumors. Analyzing the nuclear and cytoplasm expression levels, we observed a significant increase in XPO-1 expression in the nucleus in cancer (3.24 ± 3.22) and BPH (1.33 ± 0.83) with p < 0.01 (Fig. 1b) and in Gleason scores > 7 when compared to Gleason scores ≤ 7 (5.27 ± 3.24 vs 2.88 ± 3.31, p < 0.001) and 30/49 [61.2 %] vs 16/50 [32 %] cases with high IRS (P < 0.001, Fig. 1c). The analysis performed on cytoplasm revealed differences between BPH (3.45 ± 1.07) and PCa (5.61 ± 3.22, P < 0.001, Fig. 1b) but no significant differences between values of IRS measured for Gleason scores >7 (5.91 ± 3.20) and ≤ 7 (4.88 ± 3.70, P = 0.086) or the percentage of cases with high IRS [36/49 (73.5 %) vs 28/50 (56 %)] as shown in Fig. 1c. Although the mean GIRS values showed no significant differences, the percentage of cases with high XPO-1 expression was significantly higher in primary tissues derived from metastatic compared to those observed in non metastatic cases. No statistical difference was observed in the comparisons with pathologic stage for nuclear or cytoplasm IR values. Nevertheless all metastatic lesions presented elevated GIRS and nuclear IRS for XPO-1.Fig. 1

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