Young seniors looking back from 2050 to June 2021:

Promoting apoptosis in tumor cells for cancer treatment

Text: Mitchell Rikken ‘Finalist Nationale Scheikunde Olympiade 2021’  Photo: Fakurian design
10 june 2050

Hi, I'm Dr. Rikken. Together with my research group, I conduct research at the molecular level into cancer and possibilities to cure cancer. In this article I will explain the breakthroughs in cancer research my research group has made over the past 25 years. but first I will briefly explain what our driving force was behind this research. Cancer is a terrible disease, it harms you not only physically but also mentally. You are faced with a big question: will I survive? And if not, how long do I have left? These are questions that can hurt you a lot. So my research group and I wanted to offer help to people suffering from this nasty disease.

A lot of things go wrong at a molecular level in tumor cells. For example, tumor suppressor genes have been mutated, which can have disastrous consequences through, for example, incorrect amino acid incorporation. One of these consequences is that the 3D structure of the protein has changed in such a way that the protein can no longer perform its original function. The function of the tumor suppressor protein p53 is to initiate apoptosis = cell death after DNA damage. Unfortunately, this does not happen when p53 is dysfunctional. Well, this is not a super big problem, as long as other genes that play a key role in the development of cancer remain "whole". Now my research group and I have developed a molecule capable of inducing apoptosis in tumor cells. We were faced with a challenge here, how do you specify the treatment so that the apoptosis is only limited to the tumor cells? How do you get the molecule into the tumor cells? These are important points to keep in mind. 

First, we looked at how we could ever get the connection into the cell. For this we have developed a so-called “capsule” of phospholipids, the polar heads allow the capsule to dissolve in the blood. The capsule has a cell membrane-like structure, thus allowing fusion with the cell membrane of the tumor cell. To investigate whether uptake of this capsule by cells was possible, my research group radiolabeled the capsule with fluorine. Then injected into the bloodstream of mice and looked at whether fluorescence from tissues was detectable, the results turned out to be promising. After the first animal experiments, we went further, looking at how molecular adaptation ensures that only tumor cells take up the capsule. My research group and I saw that tumor cells express certain proteins on the cell surface that “normal” cells do not express. After further research, these proteins were found to have many cysteine ​​units at the end with SH groups in the side chain. We have placed a binding domain on the surface of the capsule that fits on the end of the proteins of the tumor cells, in this domain COOH groups exist that can form thioester bonds with the SH groups of the tumor proteins. 

To test whether our plan works, my research group and I damaged the DNA of astrocytes, causing these cells to divide rapidly and uninhibited, the medium of these cells almost resembled the environment in which brain tissue is located. We then blotted the tumor cells to our capsule 2.0, which was also somewhat radio labelled. The results were again promising. Finally, the synthesis of our substance, the substance that is supposed to induce apoptosis, started. The substance inhibits the compound bcl2, which is a compound that inhibits the relase of cytochrome c from mitochondria. By inhibiting the inhibitor, cytochrome c will enter the cytoplasm and induce apoptosis. Our setback was that we could not quite find where the active site of bcl2, after long research, we found out and designed a connection to a domain that binds bcl2 to the active site and thus inhibits it. The compound itself also has a nonpolar domain so that it can interact with the nonpolar tails of the capsule. After many animal experiments and tests on cancer patients, we received legal approval from the EMA in 2048. Our method is used in hospitals as a therapy for cancer patients. This was obviously a breakthrough in cancer research.

Mitchell Rikken  ‘Finalist Nationale Scheikunde Olympiade 2021’
Fakurian design

We were faced with a challenge here, how do you specify the treatment so that the apoptosis is only limited to the tumor cells?