Cisplatin has been used to treat cancer since the 1970s. Since then, many other platinum cytostatic drugs have been developed, such as triplatinNC, a superficial building block containing three platinum-bridged atoms. Unlike cisplatin, this drug also inhibits metastasis. The reason for this appears to be the geometric modeling of the sugar component of hepan sulfate, an important part of the extracellular matrix, reports a research team in the journal Cemie Angewandte.
Heparin sulfate, a glycosaminoglycan, is a series of ring-shaped sugar molecules. It is involved in many regulatory processes, as well as tumor growth and metastasis. For tumors to grow and form metastases, the extracellular matrix must be broken up in specific places to allow cells to migrate. Hepatic sulfate cleavage by the heparanase enzyme and release of specific growth factors binding to hepan sulfate play an important role in this process.
To shed light on the interaction of hepan sulfate with triplatinNC, a team led by Anil K. Gorle, Susan J. Berners-Price, and Nicholas P. Farrell at Griffith University (Brisbane, Australia), and the Commonwealth University of Virginia and Massey Cancer Center (Richmond, Virginia, USA), using fondaparinux (FPX), a molecule composed of five sugar units, as a model for hepan sulfate. A combination of computational calculations and experimental data showed that triplatinNC alters the geometry of a specific sugar component of hepan sulfate (iduronic sulfated acid). The hexagonal ring of iduronic acid can take on two spatial concentrations: a chair shape or a turntable form. In Free FPX, the seat and towel forms are in a ratio of 35:65. In the presence of triplatinNC, this moves to 75:25. In their now-preferred chair form, there is a pocket in which the platinum drug fits well, allowing it to attach strongly. In true hepan sulfate, the result of the strong binding with triplatinNC is its effective inhibition of heparanase ingestion.
Tumor cell line in a synthetic extracellular matrix served as a model for triple-negative breast cancer, which is an aggressive form of cancer that is particularly difficult to treat. Treatment with heparinase initiated significant cell migration in the model. Preoperative treatment with triplatinNC significantly reduced cell migration – an effect not seen with cisplatin. The team was also able to test the anti-metastatic activity of triplatinNC in experiments with mice.
TriplatinNC therefore exhibits double activity. In addition to a cytotoxic effect caused by its action on DNA, an anti-metastatic effect is caused by an effect on hepan sulfate activity. This opens up new opportunities for complex anti-metastatic platinum design.
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About the Author
Dr. Anil Gorle is a Research Fellow at the Institute for Glycomics at Griffith University Australia, where his research interests in metalloglycomics were developed as part of a long-term collaboration between Professors Sue Berners-Price and Nicholas Farrell of Virginia Commonwealth University, USA.
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