2. Academic Validation
  3. Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins

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

  • BMC Cancer. 2018 Aug 10;18(1):809. doi: 10.1186/s12885-018-4704-z.
Lan Lan 1,  Hao Liu 1 2,  Amber R Smith 1,  Carl Appelman 1,  Jia Yu 1 3,  Sarah Larsen 1,  Rebecca T Marquez 1,  Xiaoqing Wu 1,  Frank Y Liu 1,  Philip Gao 4,  Ragul Gowthaman 5,  John Karanicolas 6,  Roberto N De Guzman 1,  Steven Rogers 7,  Jeffrey Aubé 7,  Kristi L Neufeld 1,  Liang Xu 8 9
Affiliations

Affiliations

  • 1 Departments of Molecular Biosciences, University of Kansas, 4002 Haworth Hall, 1200 Sunnyside Avenue, Lawrence, KS, 66045-7534, USA.
  • 2 Current address: School of Pharmacy, Southwest Medical University, Luzhou City, China.
  • 3 School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China.
  • 4 Protein Production Group, NIH COBRE in Protein Structure and Function, Lawrence, USA.
  • 5 Center for Computational Biology, University of Kansas, Lawrence, Kansas, USA.
  • 6 Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 7 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • 8 Departments of Molecular Biosciences, University of Kansas, 4002 Haworth Hall, 1200 Sunnyside Avenue, Lawrence, KS, 66045-7534, USA. xul@ku.edu.
  • 9 Department of Radiation Oncology, University of Kansas Cancer Center, Kansas City, Kansas, USA. xul@ku.edu.
PMID: 30097032 DOI: 10.1186/s12885-018-4704-z
Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords

Colon cancer; Gossypolone; Liposomes; Musashi; RNA-binding protein.

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