Targeting The Achilles Heel Of Cancer Cells

By targeting proteins only expressed in cancer cells and reducing drug toxicity, scientists hope to be able to fight cancer better.

AsianScientist (Mar. 31, 2014) – Two research groups at the Nanyang Technological University (NTU) in Singapore have come up with more specific ways to target cancer cells.

While anti-cancer chemotherapeutics such as cisplatin and other platinum-based compounds are highly effective against certain cancers, they also cause severe side effects due to nonspecific cytotoxicity. Moreover, they seem ineffective against drug-resistant subpopulations of cancer cells, called cancer stem cells, resulting in a high rate of relapse in platinum drug-treated patients.

“The fundamental problem is: how do you selectively target cancer cells. We are starting to focus more and more on metastasis, because 90 percent of cancer patients will die from metastasis,” says Curtis Davey, Associate Professor from the School of Biological Sciences at NTU and lead author of a recent study on a new class of anti-cancer drugs.

Moving away from platinum-based drugs, Davey’s team turned to another metal known as ruthenium. They investigated two ruthenium-based drug compounds, which, though chemically highly similar, exhibited very distinct properties, activities and binding preferences.

Whereas the first compound RAED-C displayed high cytotoxicity and preferentially binds to DNA, the second agent RAPTA-C primarily binds to histone proteins and exhibits remarkably low cytotoxicity. The big difference in binding preferences was caused by small steric differences in the compounds’ structures.

At about the same time as Professor Davey’s group, a research team led by Associate Professor Peter Dröge, also from the NTU School of Biological Sciences, studied the function of a human chromatin protein factor – named high-mobility group AT-hook 2 (HMGA2).

HMGA2 is only expressed in embryonic stem cells and absent from normal body cells. However, HMGA2 is highly expressed in most malignant human cancers and expression levels are strongly correlated with tumor malignancy, progression into metastatic stages and the patients’ prognostic index.

The study found that HMGA2 binds to and protecting regions of single-stranded DNA from DNA breaks during replication processes. Cancer cells ‘hijack’ this DNA preservation mechanism of embryonic stem cells to evade DNA and cell destruction when exposed to chemotherapeutics.

“This survival strategy of cancer cells could potentially also be their Achilles heel,” says Dröge. “Since HMGA2 is absent from all body tissues in adult humans, drugs specifically targeting HMGA2 would be highly specific for cancer cells.”

Dröge’s team aims to develop high-throughput screening assays to detect chemical compounds interfering with HMGA2’s binding ability in collaboration with industry partners. The researchers are aiming at a combination strategy that also includes DNA damaging compounds, since inhibition of HMGA2 alone does not kill cancerous cells.

The articles can be found at:
Adhireksan et al. (2014) Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity.
Yu et al. (2014) Chaperoning HMGA2 protein protects stalled replication forks in stem and cancer cells.

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Source: Nanyang Technological University; Photo: Yu Haojie/Peter Dröge/NTU.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Nicola Wittekindt received a PhD in Molecular Toxicology from the Federal Institutes of Technology (ETH) Zürich, Switzerland, and a MSc in Biology from the University of Konstanz, Germany. She is currently a science writer at the Nanyang Technological University in Singapore.

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