Creatine potential to fight against cancer
Creatine, the organic acid that is popularly taken as a supplement by athletes and bodybuilders, serves as a molecular battery for immune cells by storing and distributing energy to power their fight against cancer, according to new research by the University of California, Los Angeles, which published in the Journal of Experimental Medicine.
For the study, researchers led by Lili Yang, PhD, the study’s senior author, expanded on previous research into the metabolic needs of tumor-infiltrating lymphocytes, immune cells that travel into tumors to fight cancer. Examining these cells, the team observed that CD8 T cells, also known as killer T cells, the foot soldiers of the immune system, taken from inside of tumors possessed a large number of creatine transporter molecules, which sit on cells' surfaces and control creatine uptake into cells.
The lab genetically engineered mouse models so that their killer T cells were deficient in a gene called CrT, or Slc6a8, which is responsible for producing creatine transporter molecules. They found that mice whose killer T cells could not take in creatine were less capable of fighting tumors.
The team then tried validating their hypothesis from the opposite angle, giving non-engineered mice a daily dose of creatine comparable to the safe dose recommended to athletes and bodybuilders. This creatine boost, which was given to some mice via injection and others as an oral supplement, made both groups better equipped to suppress both skin and colon cancer tumor growth.
Next, the team tried combining creatine supplementation with PD-1/PD-L1 blockade therapy, a form of cancer immunotherapy that prevents T cell exhaustion and has been approved to treat a broad range of cancers including melanoma, lymphoma, colon, lung, liver, kidney, and cervical. They found that creatine supplementation and anti-PD-1 blockade therapy worked synergistically, tipping the metabolic scales in T cells' favor and enabling them to avoid exhaustion and fight cancer effectively for an extended period.
Four out of five mice that received this combination therapy were found to have completely eradicated their colon cancer tumors and remained tumor-free for over three months. Furthermore, when they were given a second round of tumor cells, all the "cancer survivor" mice were protected from tumor recurrence and remained tumor-free for an additional six months.
The study shows that creatine uptake is critical to the anti-tumor activities of killer T cells. The researchers also found that creatine supplementation can improve the efficacy of existing immunotherapies.
As a next step, the team is repeating these experiments using special mouse models that harbor human tumor grafts and human immune cells. If they can replicate these effects in human cells, the team will work to determine the proper dose, timing and method to give people creatine supplements to enhance existing immunotherapies. Because the strategy has proven effective in mouse models of both melanoma and colon cancer, the team expects the findings could apply to a range of cancers.
The experimental combination therapy described above was used in preclinical tests only and has not been tested in humans or approved by the U.S. Food and Drug Administration as safe and effective for use in humans. This newly identified therapeutic strategy is covered by a patent application research group.
The researchers recommend that people consult a doctor before incorporating a new supplement such as creatine into their routine as supplements can carry risks of drug interactions and other harmful side effects. There is concern that long-term use of creatine at high doses could damage the liver, kidneys, or heart.