Antiangiogenic platinum through glycan targeting

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Biochemistry

Background:

• Heparan sulfate (HS) plays critical roles in cellular processes.
• Polynuclear platinum complexes (PPCs) are investigated for anti-cancer properties.

Purpose of the Study:

• To identify a new biological role for platinum compounds.
• To establish HS as a target for metal-based drugs.
• To explore PPCs as inhibitors of heparanase and growth factor interactions.

Main Methods:

• Investigated PPC interaction with HS using Fondaparinux as a model.
• Assessed inhibition of heparanase (HPSE) activity.
• Measured fibroblast growth factor (FGF-2) binding to HS.
• Analyzed downstream signaling via phospho-S6 ribosomal protein in HCT-116 cells.
• Evaluated inhibition of cell invasion and angiogenesis.
• Performed competition assays with Fondaparinux and TriplatinNC for DNA binding.

Main Results:

• PPCs bind to HS, inhibiting heparanase and FGF-2 binding.
• Metalloshielding of HS by PPCs effectively blocks critical HS functions.
• Inhibition of HPSE and FGF-2 signaling reduced HCT-116 cell invasion and angiogenesis.
• Fondaparinux can displace PPCs from DNA, indicating strong PPC-HS interactions.

Conclusions:

• HS is a receptor for PPCs, enabling a new class of metal-based anti-cancer drugs.
• PPCs can be repurposed from cytotoxic agents to anti-metastatic therapeutics by targeting HS.
• This approach offers a novel strategy for developing platinum-based chemotherapeutics with reduced toxicity.