Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemical Biology

First Advisor

Dr. Nicholas Farrell

Second Advisor

Dr. Matthew Hartman

Third Advisor

Dr. Jennifer Koblinski

Fourth Advisor

Dr. John Ryan

Fifth Advisor

Dr. T.A. Cropp

Abstract

Abstract

Heparan Sulfate, A New Target for Platinum in Metastatic TNBC

Author: Samantha J. Katner, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Virginia Commonwealth University, 2018

Advisor: Dr. Nicholas Farrell, Professor, Chemistry Department

Heparan sulfate proteoglycans (HSPGs), composed of the linear polysaccharide heparan sulfate (HS) conjugated to a protein core, are located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation, which constitutes the molecular recognition motif for many HS-protein interactions. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis.1 Sulfate clusters on the glycan backbone also mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding.2 The biological consequences of metalloshielding will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to the inhibition of DNA-protein binding through modification of DNA structure and conformation. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis.

PPCs are dual-function agents through their interactions with both nucleic acids and HS. The novel Pt-HS interactions open up new areas of metalloglycomics and potential anti-angiogenic activity. Here, we report PPC interactions with HS-like models: Fondaparinux (FPX)3 and heparin4. We demonstrate TriplatinNC high affinity to heparin in biophysical studies and compare HS interactions with DNA and HS using competition assays.3,4 these approaches may be extended to a range of metal-ammine compounds.4

The biological consequences of PPC-HS interactions include modulation of heparanase cleavage of FPX,3 growth factor binding to HS, and growth factor-induced migration and signaling in breast cancer and endothelial cells, as potential anti-metastatic and anti-angiogenic effects in vivo. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models.5–7 Already, PPC-HS interactions have major biological consequences in the aggressive metastatic TNBC mouse models. Impressively, PPCs reduce overall tumor metastases with emphasis in lung, bone, and liver locations in both immunocompetent and immunosuppressive mouse models. PPCs demonstrated permeability through the blood brain barrier (BBB) implying further applications for PPCs. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting. Together, these results suggest that strong PPC-HS interactions have a significant role in the inhibition of breast cancer metastases, particularly in metastatic TNBC patients.

1. Peterson, E. J. et al. Antiangiogenic platinum through glycan targeting. Chem. Sci. 8, 241–252 (2017).

2. Mangrum, J. B. et al. A new approach to glycan targeting: enzyme inhibition by oligosaccharide metalloshielding. Chem. Commun. (Camb). 50, 4056–8 (2014).

3. Gorle, A. K. et al. Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate. Chem. Eur. J (2018). doi:10.1002/chem.201706030

4. Katner, S. J., Johnson, W. E., Peterson, E. J., Page, P. & Farrell, N. P. Comparison of Metal–Ammine Compounds Binding to DNA and Heparin. Glycans as Ligands in Bioinorganic Chemistry. Inorg. Chem. acs.inorgchem.7b03043 (2018). doi:10.1021/acs.inorgchem.7b03043

5. Katsuta, E., Peterson, E. J., Katner, S. J., Farrell, N. P. & Takabe, K. Triplatin preferably suppress lung metastasis of breast cancer, and peritoneal carcinomatosis of colon and pancreatic cancer. Proc. AACR Washingt. D.C. Abstract #5117 (2017).

6. Katner, S. J. et al. Heparan sulfate , a new target for platinum in metastatic TNBC. Proc. AACR Chicago, Abstract #3941 (2018).

7. Katner, S. J. et al. Anti-metastatic platinum through glycan targeting in breast cancer. Proc. AACR Washingt. D.C. Abstract #17 (2017).

8. Silva, H. et al. Heparan sulfate proteoglycan-mediated entry pathway for charged tri-platinum compounds. Differential cellular accumulation mechanisms for platinum. Mol. Pharmacol. 9, 1795–1802 (2012).

9. Peterson, E. J. et al. Nucleolar targeting by platinum: P53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction. Mol. Pharm. 12, 287–297 (2015).

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-10-2018

Available for download on Tuesday, May 09, 2023

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