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Resistance against chemotherapeutics

Many cancers are difficult to treat with drugs (chemotherapeutics) because they are, or have become, resistant to these drugs during therapy. The cancers are often resistant against a large number of chemotherapeutics (multidrug resistance). The research group led by Johanna Weiß at the University Hospital of Heidelberg is investigating the molecular mechanisms of multidrug resistance and has the goal to optimise and individualise the chemotherapeutic treatment of cancer patients.

Tumour cells without multidrug resistance. The cells were treated with a chemotherapeutic that emits light when exposed to laser light. The photo clearly shows that the drug accumulates only in tumour cells that are not resistant to it (strong luminescence). (Figure: Work group Dr. Johanna Weiß)
The resistance of tumours against several drugs is a major problem in the chemotherapeutic treatment of cancer patients and is often associated with a bad treatment outcome. It is known that certain proteins (drug transporters) contribute considerably to this phenomenon. These transporters are located in the cell membrane and can pump the drugs out of the tumour cells. Two of the most important drug transporters, which might lead to multidrug resistance, are G-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP).

In order for Pgp and BCRP to be active, the proteins require a specific environment in the cell membrane. These cell membrane areas (microdomains) contain a large quantity of fat molecules (e.g., cholesterol) and proteins (e.g., caveolins). Johanna Weiß and her team of researchers have recently shown that the activity of Pgp and BCRP is affected by the cholesterol concentration in the membrane. Decreasing cholesterol leads to a reduction of the transport ability of these proteins. Besides for that, the interaction with certain proteins, e.g., caveolin-1, seems to be important for the activity of these transporters. Caveolin-1 is also assumed to have an important role in tumour genesis and development.
Multidrug-resistant tumour cells - the resistant cells do not emit much light upon the addition of an anticancer drug to the cell culture. (Figure: Work group Dr. Johanna Weiß)
The work group of Dr. Weiß now hopes to clarify how caveolin-1 affects the activity of Pgp and BCRP and the importance of the interaction of these molecules for cells to become resistant to anti-cancer drugs. The caveolin-1 gene will be switched off or overexpressed in selected cell lines. The researchers will subsequently examine the changes in the activity and localisation of Pgp and BCRP along with the effects on the cells’ resistance to chemotherapy.

To improve the prognosis of patients with tumours of a different origin, it is important to clarify the causes and mechanisms of multidrug resistance and find ways to increase the cells’ sensitivity to drugs. The results on the potential interrelation of drug transporters and treatment outcome are not satisfactory yet. According to state-of-the-art knowledge, this might be due to the fact that the interaction between transporters and caveolin-1 has not been taken into account. It is, therefore, absolutely important to gain deeper insights into the molecular mechanisms of the interaction of drug transporters and Cav-1, and hence into the pathophysiology of multidrug resistance and come one step closer to individualised cancer therapy.

Dr. Weiß is the head of the Molecular Biology and Biochemistry Laboratory in the Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, at the University of Heidelberg.

This research project is supported by the Wilhelm Sander Foundation with more than 100,000 euros in funding. The foundation supports medical research, in particular projects that focus on cancer treatment. Since the establishment of the foundation in 1974, more than 160 million euros have been granted for research projects in Germany and Switzerland. Wilhelm Sander endowed all his money to the foundation when he died in 1973.

Source: Wilhelm Sander Foundation - 13 August 2008
Further information:
Dr. Johanna Weiß
Department of Internal Medicine VI
Clinical Pharmacology and Pharmacoepidemiology
University of Heidelberg
E-mail: johanna.weiss@med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/resistance-against-chemotherapeutics