Starving cancer cells

Sweets make many people happy, and many people admit to being downright addicted to sugar. In the case of cancer cells, it even goes beyond this: many cancer cells cannot multiply without sugar. Sugar in the form of glucose fulfills a variety of functions in the cell: It serves as an energy source and provides building blocks for biomolecules that are necessary for cell division and growth.

Many cancer cells divide very quickly and therefore need particularly high amounts of glucose. Normally, in the presence of oxygen, it is utilized highly efficiently and with maximum energy output. However, if there is a lack of oxygen, only ca. one sixth of the energy can be obtained. Although cancer cells do not always lack oxygen, they prefer the more inefficient utilization pathway, because it supplies the energy and building blocks needed for rapid growth many times faster than the conventional one. However, in order to compensate for inefficient utilization, a tumor cell needs about 10 times the amount of sugar. This phenomenon was described by Max Planck scientist Otto Warburg almost 100 years ago. His discovery laid the foundation for modern imaging techniques in cancer diagnostics, such as positron emission tomography (PET). It makes visible where in the body increased sugar is absorbed. Thus, the location and stage of the tumor can be determined.

But how does the sugar get into the cells? Glucose is highly water-soluble and can therefore be transported to the cells via the blood without any problems. Various glucose transporters (GLUT) are then responsible for uptake into the cells. Cancer cells have an exceptionally high amount of the transporter GLUT-1, which ensures a high sugar supply.

Nature as a model

We want to take advantage of the cancer cells’ sugar addiction to fight them. Like searching for a needle in a haystack, we have a library of more than 150.000 chemical substances searched for active ingredients that prevent glucose transport in cells. We came across three candidates that block both the transporter GLUT-1 and GLUT-3. Two of these candidates are derived from natural products. These substances developed by nature serve numerous species, for example, as defense or to attract mates. Many natural substances have also been shown to be drugs for humans, such as the opiate morphine from the opium poppy or the penicillin antibiotics from fungi. In this way, nature has long served as an inspiration to drug researchers for the development of new active ingredients. Nowadays, research is able to go one step further: we can develop substances similar to natural substances, which do not occur in nature in this way. By first analyzing the basic building blocks of all known natural products and then combining them in a novel way, we produced pseudo-natural products that can inhibit glucose transport.

Growth-inhibiting effect even in cell clusters

In experiments with cell cultures, our substances actually had the desired effect: the glucose deprivation caused by the active ingredient (GLUT inhibitor) slowed down the growth of cancer cells – which ultimately died. We found that while various types of cancer cells were attacked, healthy cells were spared.

Compared with two-dimensional cell culture, a tumor is a three-dimensional cell structure in which the outer cells have better access to nutrients than the cells on the inside. In order to represent the events in the tumor as realistically as possible, we have also used the GLUT inhibitor in 3D cell structures, so-called

spheroids. Surprisingly, the active ingredient also led to a slowing of growth in this case. Consistent with results from cancer research, which showed that the utilization of glucose is needed mainly in the center of the tumor, it was mainly the cells inside the spheroids that died.

No loophole for cancer cells

But unfortunately, tumors are not always so easy to outsmart. It is not uncommon for drug resistance to develop in a therapy, or for cancer cells to find a loophole. Because to maintain vital processes, cells have evolved sophisticated mechanisms that can bypass interference. In the case of glucose deficiency, z.B. other nutrients, such as glutamine, are also utilized. As a natural amino acid, glutamine is not only one of the 21 building blocks that make up proteins, but also an important key metabolite. We therefore treated cancer cells with a combination of our GLUT inhibitor and an inhibitor of glutamine utilization, which actually had an enhanced growth-inhibiting effect.

Fig. 1: Healthy cells (red) metabolize glucose in the presence of oxygen. This process is very efficient, but slow. Cancer cells (purple) grow particularly fast. They metabolize sugar without oxygen. This recovery is much more inefficient, but all the faster (so-called Warburg effect). The inefficient utilization is compensated by a massively increased sugar intake. Cancer cells produce a particularly large number of glucose transporters (GLUTs), especially GLUT-1. Our GLUT inhibitors block sugar transporters in cell culture experiments and thus inhibit sugar uptake. This starves the cancer cells and they die.

© Max Planck Institute of Molecular Physiology/Ziegler

Fig. 1: Healthy cells (red) metabolize glucose in the presence of oxygen. While this process is very efficient, it is slow. Cancer cells (purple) grow particularly quickly. They metabolize sugar without oxygen. This
Recovery is significantly less efficient, but all the faster (so-called Warburg effect).
The inefficient recovery is offset by a massive increase in sugar intake. For this cancer cells produce particularly many glucose transporters (GLUTs), especially GLUT-1. Our GLUT inhibitors block the sugar transporters in cell culture experiments and thus inhibit sugar absorption. This starves the cancer cells and they die.

Increased production of the glucose transporter GLUT-3 provides another fallback option for tumor cells in the face of glucose deficiency. Since our GLUT inhibitor also blocks GLUT-3 in addition to GLUT-1, this protective mechanism of cancer cells is also bypassed.

Cancer remains one of the leading causes of death worldwide. Numerous research groups are working intensively on starting points for new treatment options. Cancer research has gained many new insights and transferred innovative strategies from basic research to clinical practice. In this way, the survival chances of cancer patients have almost doubled in the last 50 years. At present, our GLUT inhibitors are being developed into so-called lead structures at the Lead Discovery Center in Dortmund, Germany, founded by the technology transfer organization MaxPlanck Innovation – a first step on the long road to becoming a drug.

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