DNA is the basic blueprint for everything in a cell, providing the nucleotide sequence that encodes all the proteins and regulatory factors that are essential for proper cell function. Damage to that DNA can happen through all sorts of mechanisms, including the radiation that is used to treat cancer. Cell cycle progression and DNA repair are the two ways in which a cell tries to fix DNA damage.
"With radiation, the DNA is injured, resulting in single or double strand DNA breaks. When this happens the cell senses the DNA damage and has a very complicated way of responding," explains Dr. Saba.
First, the cell’s ability to proliferate or split into two cells, also referred to as the cell cycle, pauses temporarily. This is called cell cycle arrest. Second, the cell uses this extra time to repair the DNA through the activation of various DNA repair mechanisms.
“For the first time, we’ve demonstrated that the metabolism of S1P seems to have a direct role in regulating cell cycle response to radiation and DNA damage repair. By inhibiting SPL, we seem to impact the cell cycle control and DNA repair pathways that keep cells alive,” says Dr. Saba.
“For the first time, we’ve demonstrated that the metabolism of S1P seems to have a direct role in regulating cell cycle response to radiation and DNA damage repair.”
In addition, Dr. Saba's studies also provide first time evidence that when SPL does breakdown S1P, SPL turns S1P turns into a toxic aldehyde, called trans-2-hexadecenal.
"Trans-2-hexadecenal actually increases cell death," says Dr. Saba. "This means that using an SPL inhibitor to both increase S1P levels and decrease the degradation of S1P actually provides a double whammy in terms of increasing protection.”
Currently, there are already two known related compounds that function as SPL inhibitors, one of which is an FDA-approved food additive and the other which is being tested in clinical trials for immune modulation. Neither inhibitor has yet been approved for use in radiation therapy. However, this is something Dr. Saba and her colleagues are exploring. Alternatively, Dr. Saba is also exploring potential ways of making cancer cells more sensitive to radiation, by finding a method to get them to express SPL and thereby heighten their sensitivity to chemotherapy and radiation.
“We hope to eventually be able to use SPL to help cancer patients in two ways,” says Dr. Saba. “We could use an inhibitor to decrease SPL levels and thereby protect the DNA of patients' normal cells during cancer radiation, or we could find a way to make cancer cells express more SPL to increase tumor shrinkage after radiation.”
In the meantime, however, Dr. Saba and her colleagues have provided new evidence of the mechanisms behind SPL and how it can be effectively leveraged in the fight against cancer.