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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 in prostate cancer models

Overview of attention for article published in BMC Cancer, December 2015
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2 tweeters

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15 Mendeley
Title
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
Published in
BMC Cancer, December 2015
DOI 10.1186/s12885-015-1936-z
Pubmed ID
Authors

Giovanni Luca Gravina, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Dilara McCauley, Michael Kauffman, Sharon Shacham, Claudio Festuccia

Abstract

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. 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. 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.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 15 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 15 100%

Demographic breakdown

Readers by professional status Count As %
Unspecified 4 27%
Researcher 4 27%
Student > Ph. D. Student 2 13%
Student > Master 2 13%
Student > Doctoral Student 1 7%
Other 2 13%
Readers by discipline Count As %
Agricultural and Biological Sciences 3 20%
Unspecified 3 20%
Biochemistry, Genetics and Molecular Biology 3 20%
Medicine and Dentistry 3 20%
Pharmacology, Toxicology and Pharmaceutical Science 1 7%
Other 2 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 December 2015.
All research outputs
#4,663,361
of 6,632,903 outputs
Outputs from BMC Cancer
#1,712
of 3,124 outputs
Outputs of similar age
#159,694
of 252,576 outputs
Outputs of similar age from BMC Cancer
#115
of 239 outputs
Altmetric has tracked 6,632,903 research outputs across all sources so far. This one is in the 26th percentile – i.e., 26% of other outputs scored the same or lower than it.
So far Altmetric has tracked 3,124 research outputs from this source. They receive a mean Attention Score of 3.2. This one is in the 36th percentile – i.e., 36% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 252,576 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 31st percentile – i.e., 31% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 239 others from the same source and published within six weeks on either side of this one. This one is in the 43rd percentile – i.e., 43% of its contemporaries scored the same or lower than it.