UCLA Researchers in the Department of Chemistry and Biochemistry have devised a novel off label usage for the commonly available supplement s-adenylmethionine in the treatment of cancer.
BACKGROUND:
Tumor cells exhibit a wildly different metabolism from the tissue they are derived from. This altered metabolism allows sustained proliferation rates while avoiding common cell death signaling, leading to rapid tumor growth. Common mechanisms that tumors utilize to create altered metabolic profiles include: mutation, post-translational inactivation of enzymes, or substitution of different enzyme isoforms. It therefore comes as no surprise that developments are currently underway to target metabolic pathways for cancer therapy. One promising cancer therapeutic lead stems from the observation that cancer cells often display overexpression of enzymes that modify arginine residues; this modification allows cancer cells to rewire protein-protein interactions, allowing beneficial energetic pathways to be over utilized compared to healthy cells. The most currently studied enzyme that allows methylation of the arginine residues is PRMT5 and has had many associated clinical trials for the development of therapeutics that can deregulate its function. Agios pharmaceuticals has recently developed a small molecule drug that can lower PRMT5 function by targeting the expression of an upstream metabolite called s-adenylmethionine. However, as with many metabolic targeting therapeutics, there is concern with a low therapeutic index: a comparison of the amount of therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.
INNOVATION:
UCLA Researchers in the Department of Chemistry and Biochemistry have devised a novel off label usage for the commonly available supplement s-adenylmethionine in the treatment of cancer. S-adenylmethionine when taken orally is non-cell-permeable, but when metabolized in the blood to 5’-methylthoadenosine (MTA), is able to traverse the cell membrane. Accumulation of MTA leads to a secondary metabolism in cells to adenosylhomocysteine which acts as an inhibitor to PRMT5. The oral use of s-adenylmethionine is a marketed dietary supplement currently used for depression and liver disease, but these observations also make it an attractive candidate for cancer therapy. Due to its natural occurrence in the body, the use of s-adenylmethionine may serve as a potent therapy in targeting tumor metabolism with a high therapeutic index. Additionally, its use with current clinical trial candidates could be highly promising. The presented off label usage of s-adenylmethionine serves as an attractive candidate for targeting hyperpolarized tumor metabolism due to its high therapeutic index and wide availability.
POTENTIAL APPLICATIONS:
• The specific targeting of arginine residue methylation in a wide variety of cancer cells
• The synergistic combination of s-adenylmethionine and currently studied clinical candidates for targeted PRMT5 activity
ADVANTAGES:
• Natural biomolecule that may promise high therapeutic index for cancer treatment
• Wide availability due to use for depression, and liver disease treatment
• Ability to further augment the effectiveness of other drugs that target PRMT5
DEVELOPMENT-TO-DATE:
The off-label usage of s-adenylmethionine is currently being studied to determine its effectiveness as a cancer therapeutic.
RELATED PAPERS:
Steven G. Clarke (2006) “Inhibition of Mammalian Protein Methyltransferases by 5’-Methylthioadenosine (MTA): A Mechanism of Action of Dietary SAMe?” In “The Enzymes” Volume 24 “Protein Methyltransferases” pages 467-493, Academic Press, New York.