Antiangiogenic platinum through glycan targeting

Abstract

The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan sulfate results in modulation of the biomolecule signaling functions leading to inhibition of angiogenesis.

Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

“…In general, the identification and acceptance of DNA as molecular target has dominated mechanistic studies on platinum‐based anticancer agents yet the ability to systematically target membrane biomolecules suggest approaches to drug design that can play a significant role in dictating the overall biology of platinum drugs and have functional consequences contributing to the overall cytotoxic profile of platinum agents. Newer agents of clinical relevance can emerge from emphasis and recognition of inherently multifunctional cellular action …”

“…The over‐expression of glycans on many tumor surface membranes further affords a molecular approach to tumor selectivity for PPCs . The high affinity of PPCs for glycans can have consequences for HSPG function and can lead to potentially anti‐angiogenic and anti‐metastatic platinum complexes . It is therefore relevant to study the membrane interactions of PPCs, and indeed platinum‐based agents in general, to describe as fully as possible the cellular interactions contributing to the observed cytotoxic (antitumor) events.…”

Substitution‐Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate

“…The sulfate residues are the critical recognition features for HS interaction with protein substrates such as growth factors. We have recently shown that sulfate cluster masking, or “metalloshielding”, by clinically relevant anticancer polynuclear platinum complexes (PPCs)—Triplatin (BBR3464) and its substitution‐inert analogue TriplatinNC—is an effective way to protect HS from the actions of its associated enzymes and proteins . By protecting the substrate, the shielding concept is a complementary and attractive alternative to the time‐consuming synthesis of small oligosaccharides, which are generally designed to act as competitive inhibitors toward heparanase .…”

Metal ions and the extracellular matrix in tumor migration

“…ESI‐MS analysis of Mn 2+ –FPX interaction (A). Mn 2+ can compete with Na + and protect against SO 3 loss (B) .…”

“…Metalloshielding is strong enough to prevent bacterial heparinase and human HPSE cleavage of FPX in a charge‐dependent manner . Metalloshielding prevents growth factor binding to HS and growth factor receptor recruitment with consequent inhibition in FGF‐2‐induced downstream accumulation of pS6 ribosomal protein in human colon tumor HCT116 cells . The downstream cellular consequences include inhibition of angiogenesis as measured by the rat aortic ring assay. The angiogenic inhibition through metalloshielding is as efficient as a prototypical polysaccharide mimetic PI‐88 . Cellular accumulation of PPCs is HSPG‐mediated, a discrete mechanism not shared by cisplatin or oxaliplatin . This accumulation mechanism has relevance for tumor‐specific accumulation of platinum‐based antitumor agents .…”