Study reveals how tumors evade drugs designed to starve, kill them
A new research in cancer cells detailed how tumors evade drugs designed to starve and kill them
New York: A new research in cancer cells detailed how tumors evade drugs designed to starve and kill them.
Chemotherapies successfully treat cancers and extend patients’ lives, but don’t work for everyone for long as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs' effects, according to the study published in online journal Nature Metabolism.
Many of these drugs are antimetabolics, disrupting cell processes needed for tumor growth and survival.
Three such drugs used in the study - raltitrexed, N-(phosphonacetyl)-l-aspartate (PALA) and brequinar, that are said to work to prevent cancer cells from making pyrimidines – the molecules that are essential component to genetic letter codes, or nucleotides, that make up RNA and DNA.
Cancer cells must have access to pyrimidine supplies to produce more cancer cells and to produce uridine nucleotides, a primary fuel source for cancer cells as they rapidly reproduce, grow, and die.
Disrupting the fast-paced but fragile pyrimidine synthesis pathways, as some chemotherapies are designed to do, can rapidly starve cancer cells and spontaneously lead to them dying (apoptosis).
Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study shows how cancer cells survive in an environment made hostile by the persistent shortage of the energy from glucose (the chemical term for blood sugar) needed to drive tumor growth.
This better understanding of how cancer cells evade the drugs' attempts to kill them in a low-glucose environment, the researchers say, could lead to the design of better or more effective combination therapies.
The study results showed that the low-glucose environment inhabited by cancer cells, or tumor microenvironment, stalls cancer cell consumption of existing uridine nucleotide stores, making the chemotherapies less effective.
Normally, uridine nucleotides would be made and consumed to help make the genetic letter codes and fuel cell metabolism. But when DNA and RNA construction is blocked by these chemotherapies, so too is the consumption of uridine nucleotide pools, the researchers found, as glucose is needed to change one form of uridine, UTP, into another usable form, UDP-glucose.
“The irony is that a low-glucose tumor microenvironment is in turn slowing down cellular consumption of uridine nucleotides and presumably slowing down rates of cell death”, the researchers said.
The researchers say cancer cells need to run out of pyrimidine building blocks, including uridine nucleotides, before the cells will self-destruct.
In other experiments, low-glucose tumor microenvironments were also unable to activate two proteins, BAX and BAK, sitting on the surface of mitochondria, a cell's fuel generator. Activation of these trigger proteins disintegrates the mitochondria, and instantly sets off a series of caspase enzymes that help initiate apoptosis (cell death).
"Our study shows how cancer cells manage to offset the impact of low-glucose tumor microenvironments, and how these changes in cancer cell metabolism minimize chemotherapy's effectiveness," said study lead investigator Minwoo Nam, PhD, a postdoctoral fellow in the Department of Pathology at NYU Grossman School of Medicine and Perlmutter Cancer Center.
"Our results explain what has until now been unclear about how the altered metabolism of the tumor microenvironment impacts chemotherapy: low glucose slows down the consumption and exhaustion of uridine nucleotides needed to fuel cancer cell growth and hinders resulting apoptosis, or death, in cancer cells," said senior study investigator Richard Possemato, PhD who is associate professor in the Department of Pathology at NYU Grossman School of Medicine and also a member of Perlmutter Cancer Center.
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