Under low glucose conditions, cancer cells evade chemotherapy

Laboratory experiments with cancer cells have revealed two ways in which tumors evade the effects of drugs designed to debilitate and destroy them, a new study says.

Although chemotherapy drugs successfully treat cancer and extend patients’ lives, their effects are known to be short-lived because cancer cells skillfully rearrange their energy conversion process (metabolism) to circumvent the effects of the drugs. Many of these drugs are so-called antimetabolics, which disrupt the cellular processes necessary for tumor growth and survival.

The drugs used in the study interfere with the formation of pyrimidines, molecules that are important components of the nucleotides that make up RNA and DNA. Cancer cells must have access to pyrimidine to increase their numbers and produce uridine nucleotides, the primary fuel source for cancer cells, which multiply, grow and die rapidly. Disrupting the rapid but fragile pyrimidine synthesis pathway targeted by some chemotherapy drugs can starve cancer cells and cause them to spontaneously death (apoptosis).

The new study, led by scientists from NYU Langone Health and its Perlmutter Cancer Center, shows how cancer cells survive in a hostile environment caused by a constant lack of energy from glucose (the chemical term for blood sugar) needed for tumor growth. A better understanding of how cancer cells evade drug attempts to kill them in low-glucose environments could lead to the development of more effective combination therapies, the researchers said.

The findings, published in the journal Nature Metabolism, showed that the low-glucose environment in which cancer cells live delays cancer cells from consuming available stores of uridine nucleotides, making chemotherapy less effective by slowing the rate of cell death.

In other experiments, the low-glucose tumor microenvironment also failed to activate two proteins, BAX and BAK, located on the surface of mitochondria, the cell’s fuel generators. Activation of these trigger proteins destroys mitochondria and immediately triggers a series of caspase enzymes that help initiate apoptosis (cell death).

The study shows how cancer cells manage to compensate for the effects of a low-glucose tumor microenvironment, and how these changes in cancer cell metabolism minimize the effectiveness of chemotherapy

“The results of the study explain what has remained unclear until now, how altered tumor microenvironment metabolism affects chemotherapy: Low glucose slows the uptake and depletion of uridine nucleotides, which are essential for cancer cell growth, and inhibits apoptosis (death) of cancer cells,” said study senior investigator Richard Possemato, PhD, assistant professor of pathology at New York University Grossman School of Medicine and a fellow at Perlmutter Cancer Center.

The results of the study can be used to develop chemotherapy or combination therapies that will alter or trick cancer cells into responding to a low-glucose microenvironment in the same way they would respond to an otherwise stable glucose microenvironment.

With these findings, diagnostic tests can be developed to determine how a patient’s cancer cells will respond to a low-glucose microenvironment and predict how well a patient might respond to a particular chemotherapy.