| Title |
Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins
|
|---|---|
| Published in |
BMC Cancer, August 2018
|
| DOI | 10.1186/s12885-018-4704-z |
| Pubmed ID | |
| Authors |
Lan Lan, Hao Liu, Amber R. Smith, Carl Appelman, Jia Yu, Sarah Larsen, Rebecca T. Marquez, Xiaoqing Wu, Frank Y. Liu, Philip Gao, Ragul Gowthaman, John Karanicolas, Roberto N. De Guzman, Steven Rogers, Jeffrey Aubé, Kristi L. Neufeld, Liang Xu |
| Abstract |
The Musashi (MSI) family of RNA-binding proteins is best known for the role in post-transcriptional regulation of target mRNAs. Elevated MSI1 levels in a variety of human cancer are associated with up-regulation of Notch/Wnt signaling. MSI1 binds to and negatively regulates translation of Numb and APC (adenomatous polyposis coli), negative regulators of Notch and Wnt signaling respectively. Previously, we have shown that the natural product (-)-gossypol as the first known small molecule inhibitor of MSI1 that down-regulates Notch/Wnt signaling and inhibits tumor xenograft growth in vivo. Using a fluorescence polarization (FP) competition assay, we identified gossypolone (Gn) with a > 20-fold increase in Ki value compared to (-)-gossypol. We validated Gn binding to MSI1 using surface plasmon resonance, nuclear magnetic resonance, and cellular thermal shift assay, and tested the effects of Gn on colon cancer cells and colon cancer DLD-1 xenografts in nude mice. In colon cancer cells, Gn reduced Notch/Wnt signaling and induced apoptosis. Compared to (-)-gossypol, the same concentration of Gn is less active in all the cell assays tested. To increase Gn bioavailability, we used PEGylated liposomes in our in vivo studies. Gn-lip via tail vein injection inhibited the growth of human colon cancer DLD-1 xenografts in nude mice, as compared to the untreated control (P < 0.01, n = 10). Our data suggest that PEGylation improved the bioavailability of Gn as well as achieved tumor-targeted delivery and controlled release of Gn, which enhanced its overall biocompatibility and drug efficacy in vivo. This provides proof of concept for the development of Gn-lip as a molecular therapy for colon cancer with MSI1/MSI2 overexpression. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 50% |
| Unknown | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 42 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 7 | 17% |
| Researcher | 7 | 17% |
| Student > Master | 5 | 12% |
| Student > Bachelor | 3 | 7% |
| Other | 2 | 5% |
| Other | 3 | 7% |
| Unknown | 15 | 36% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 8 | 19% |
| Medicine and Dentistry | 5 | 12% |
| Pharmacology, Toxicology and Pharmaceutical Science | 3 | 7% |
| Agricultural and Biological Sciences | 3 | 7% |
| Neuroscience | 2 | 5% |
| Other | 4 | 10% |
| Unknown | 17 | 40% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. 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 November 2018.
All research outputs
#13,624,398
of 23,099,576 outputs
Outputs from BMC Cancer
#3,023
of 8,385 outputs
Outputs of similar age
#169,757
of 331,118 outputs
Outputs of similar age from BMC Cancer
#49
of 134 outputs
Altmetric has tracked 23,099,576 research outputs across all sources so far. This one is in the 39th percentile – i.e., 39% of other outputs scored the same or lower than it.
So far Altmetric has tracked 8,385 research outputs from this source. They receive a mean Attention Score of 4.3. This one has gotten more attention than average, scoring higher than 62% of its peers.
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 331,118 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 134 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 61% of its contemporaries.