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Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins

Overview of attention for article published in BMC Cancer, August 2018
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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, 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.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 13 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 13 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 4 31%
Unspecified 3 23%
Student > Ph. D. Student 3 23%
Other 1 8%
Student > Bachelor 1 8%
Other 1 8%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 4 31%
Unspecified 3 23%
Medicine and Dentistry 2 15%
Agricultural and Biological Sciences 1 8%
Energy 1 8%
Other 2 15%

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 14 August 2018.
All research outputs
#10,640,011
of 13,370,991 outputs
Outputs from BMC Cancer
#3,314
of 5,014 outputs
Outputs of similar age
#199,428
of 266,773 outputs
Outputs of similar age from BMC Cancer
#1
of 1 outputs
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