Scientists overpower cancer’s drug defences

Stripping cancer cells of their defences against chemotherapy with a new class of anti-resistance drug has the potential to improve treatment for many solid tumours, Cancer Research UK scientists suggest.

Cancer cells often resist the effects of treatment with the help of a molecule called P-glycoprotein, which acts as a molecular bouncer, throwing out anti-cancer drugs before they get a chance to take action.

But in a study published in the March edition of the European Journal of Cancer¹, researchers in Oxford were able to inactivate the ejection mechanism, making cancer cells vulnerable to treatment once more.

They treated cancer successfully in a number of tumour model systems, suggesting therapies to counter the action of P-glycoprotein could benefit many patients.

While chemotherapy is often effective initially against tumours, cancer cells may then adopt a number of strategies to give them resistance to treatment.

One strategy many tumours use is to produce large amounts of P-glycoprotein, apparently as a safeguard against chemotherapy. Working as a doorman, it removes unwanted materials such as anti-cancer drugs from a cell’s interior.

Scientists knew that a drug called XR9576 could block P-glycoprotein and sensitise individual cancer cells to chemotherapy, but they didn’t know if the drug would be successful against whole tumours, which can be very difficult to treat.

Cancer Research UK scientists at John Radcliffe Hospital in Oxford grew spherical balls of cells in the laboratory, in order to mimic the effects of drug treatment on tumours. There were two types of ball – one made up of cells with low amounts of P-glycoprotein, the other consisting of cells with high amounts of the molecule.

Cancer Research UK’s Dr Richard Callaghan, leading the team at John Radcliffe’s Hospital, University of Oxford, says: “The core of a tumour is an extremely hostile environment for anti-cancer drugs to work in, with a variety of barriers put up to stop drugs from taking effect.

“We wanted to know whether the ability of P-glycoprotein to throw out drugs from cancer cells was a vital component of a tumour’s resistance to treatment. They key question was, would knocking out the molecule be enough on its own to make tumours treatable once more?”

Researchers treated both types of model tumour with vinblastine or doxorubicin – two common components of chemotherapy. The balls of cells with low amounts of P-glyoprotein were, as expected, highly sensitive to both drugs. But those with high P-glycoprotein were up to 20 times more resistant to doxorubicin and up to 300 times more resistant to vinblastine.

Scientists then repeated the procedure, but this time pretreated the model tumours with XR9576. It stripped the tumours of resistance to chemotherapy, making them far more sensitive to treatment.

Dr Callaghan adds: “We knew that P-glycoprotein was found in large numbers of tumours, but we didn’t know how important the molecule was for their resistance to drugs. What we were able to show in this study was that it’s not only a key player in drug resistance, but that we can do something to counter the problem, by knocking out the molecule’s action. It raises the possibility of new types of treatment to overcome a tumour’s resistance to chemotherapy.”

Professor Robert Souhami, Cancer Research UK, Director of Clinical and External Affairs, says: “It’s very upsetting when a patient whose tumour initially seemed to be responding to chemotherapy then begins to relapse as cells become resistant to treatment.

“Cancer cells use a number of strategies for avoiding the effects of chemotherapy, but we can develop methods to overcome them. The new study has demonstrated that by overpowering one of the molecular doormen that many cancer cells employ, it is possible to leave tumours vulnerable to treatment once more. This has obvious potential implications for treatment”

ENDS

1. European Journal of Cancer40 (4) pp.594-605