Taking the first steps towards beating multidrug-resistant cancer

Newly-discovered selenocompounds block cancer cells’ defenses against chemotherapy drugs


When I was a child, I had a benign tumor and I needed surgery. Fortunately, this treatment was successful and I did not require chemotherapy or radiotherapy.

Not everybody is so lucky; there are a lot of people with cancer who require very aggressive treatments, and even those are sometimes unsuccessful. Cancer is a leading cause of death worldwide and, sadly, its incidence and mortality are rising, mainly in developed countries.

The fight against cancer has become more challenging with the rise of multidrug resistant cancers – those that have developed a defense mechanism to stop chemotherapy drugs from working. In a new paper published in Bioorganic & Medicinal Chemistry Letters, we show how some newly discovered molecules called selenocompounds can block cancer cells’ defenses against treatment, making drugs more effective.

During my PhD at the University of Navarra in Spain and Saarland University in Germany, I worked with several colleagues to synthesize selenium-containing compounds (which we call selenocompounds). Selenium is essential for our body’s cells and is found in many multivitamins. Selenium deficiency can cause the bone disorder Kashin-Beck disease and the heart disorder Keshan disease. Research has also shown that taking selenium supplements can reduce the risk of some cancers.

Our selenocompounds showed strong activity against cancer cells in the lab: they limited the growth of cancer cells, or even killed them, and stopped cancer from developing. Through a literature search we found a study that showed similar selenocompounds enhance the potency of chemotherapy drugs used in cancer treatment, so we decided to investigate more in-depth.

We wondered whether the selenocompounds were enhancing the potency of the chemotherapy drugs by interacting with their defense mechanisms somehow. When exposed to aggressive chemotherapy drugs, some cancer cells can develop defense mechanisms – one such mechanism is a protein in the cell membrane that acts like a pump and pushes the drug back out of the cell. These proteins are called efflux pumps, and one common pump is ABCB1.

Structure of the four most active selenocompounds. (Image was featured in the original research article by Domínguez-Álvarez et al in <em>Bioorganic & Medicinal Chemistry Letters</em>, June 2016)

To test this in the lab, a group at the University of Szeged in Hungary evaluated how these compounds affected modified mouse cancer cells, which have lots of ABCB1 proteins. We also had a reference chemical that can attach to the protein pumps to stop them from working. This reference chemical acts as a guide: if the molecules we were testing had the same effect, we would know they were blocking ABCB1.

Our experiments showed that the selenocompounds did attach to the ABCB1 efflux pumps, blocking them. In fact, the most active compound inhibited this protein almost four times more strongly than the reference!

We also found that the selenocompounds were able to trigger the process of cell suicide, called apoptosis, in cancer cells. The most active was just as potent as a known apoptotic compound, killing 80 percent of the cells.

The ultimate aim of cancer research is to give more chances to people whose lives are at risk due to this disease. The development of pharmaceutical drugs requires a lot of effort and time, and the results our group presents are just preliminary. We are realistic and we know that much more research needs to be done, but we are excited about these promising results that open new and unexplored possibilities.

It’s important for people to know that different groups, like us, are doing their best in their laboratories in the daily fight against cancer. Contributing my effort to this fight, even in these starting steps, fulfills me. From a personal point of view, it is very satisfying to work in the development of better treatments for cancer and, in particular, against resistant cancers.

I hope that in the future, our work will serve as the basis to develop new drugs against cancer that reach the patients who need them.

Read the study

Elsevier has made this article freely available until January 5, 2017:

Domínguez-Álvarez, Enrique et al: “Identification of selenocompounds with promising properties to reverse cancer multidrug resistance,” Bioorganic & Medicinal Chemistry Letters (June 2016)

Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience. This journal is published by Elsevier.

Image of cancer cell © istock.com/wildpixel



Written by

Enrique Domínguez-Álvarez, PhD

Written by

Enrique Domínguez-Álvarez, PhD

Dr. Enrique Domínguez-Álvarez has a PhD from the University of Navarra, Spain, and Saarland University, Germany, during which he synthesized 57 novel selenocompounds with anticancer activity. He had a postdoc position at Jagiellonian University, Poland, where he synthesized novel histamine ligands for the treatment of inflammation disorders. He will soon begin a new position at the Spanish National Research Council, where he will study more in-depth the multidrug resistance reversing activity of selenocompounds.


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