New class of chemical compounds makes cancer cells more sensitive to chemotherapy drugs
Scientists have pinpointed the relevant enzyme, identifying a new target for anti-tumour agents
Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich, Germany have identified a new class of chemical compounds that make cancer cells more sensitive to chemotherapeutic drugs. They have also pinpointed the relevant enzyme, thus identifying a new target for anti-tumour agents.
The team, led by LMU’s Professor Angelika Vollmar and Professor Stephan Sieber of the Technische Universität München (TUM), have found that the compound itself is non-toxic, but it stimulates the killing of rapidly dividing cells by chemotherapeutic drugs. This sensitising effect means that the latter can be used in lower doses, which makes it less likely that the target cells will become resistant to their lethal effect.
The work was carried out by an interdisciplinary collaboration made up of scientists from LMU, TUM and the Saarland University in Saarbrücken, and the results appear in the latest issue of the journal, Angewandte Chemie – International Edition.
Chemotherapy of malignant tumours is complicated by the fact that, over time, rapidly dividing cancer cells tend to become resistant to the drugs used.
'One way to avoid this is to administer the agent in conjunction with an otherwise innocuous compound that makes cells more vulnerable to its deleterious effects, and induces them to undergo programmed cell death,' says Vollmar, who is Professor of Pharmaceutical Biology at LMU.
Our studies show that T8 is a very promising lead compound, as it is capable of exercising a chemosensitising effect on diverse types of cancer cells
The collaborative venture has led to the discovery of a new class of chemical compounds, referred to as T8, which specifically sensitises cells to the effect of the anti-cancer drug etoposide, which inhibits the growth of tumour cells by inducing the formation of breaks in the DNA.
The scientists have also identified the protein disulfide isomerase (PDI) as the target of the new agents. PDI is an enzyme that modifies the spatial conformation, and thus the functional state, of proteins involved in a variety of cellular functions.
A major advantage of the new compound is that it is intrinsically non-toxic. Moreover, its functional impact on its target enzyme is reversible. Only when it is administered with a chemotherapeutic agent do its effects on cell metabolism become manifest.
'Our studies show that T8 is a very promising lead compound, as it is capable of exercising a chemosensitising effect on diverse types of cancer cells,' added Vollmar.
The drug has been tested on a variety of different tumour cells including leukaemia, pancreatic and breast cancer cell lines. In the next phase of the project, this new class of chemosensitisers will be tested in a variety of in-vivo animal models, and the compounds will be used to probe the functional significance of PDI as a drug target for tumour therapy.
