Exploiting leukemia stem cells’ hunger for aminoacids: old notions get new dresses
Most of animal cells rip apart sugar to release energy. Sometimes they rip apart fats, and in special circumstances, cells can even metabolize proteins. Cancer cells do things a little differently. First, most cancer cells continue to depend on glucose, but switch over from “cellular respiration” (which requires oxygen), to “glycolysis” (which can happen with or without oxygen). Researchers from University of Colorado Cancer Center are exploring a third approach: they stick with cellular respiration, but switch from metabolizing sugar to metabolizing protein, or more precisely aminoacids, which are the building blocks of protein. Healthy cells don’t need to metabolize protein. Indeed, it looks like that cancer stem cells do need to metabolize protein. And this difference is proving to be an Achilles’ heel that allows researchers to target cancer stem cells without harming healthy cells – the approach has already proven effective in clinical trials against acute myeloid leukemia and holds promise for other cancers including breast, pancreatic and liver.
For example, some aminoacids are needed for different metabolic needds other than protein synthesis. Taking the easiest example, we cite glutamine. It serves for aminosugars (present in many cellular antigens) and the synthesis of purines and pyrimidines (backbone bases for nucleic acids). It also enters the structure of glutathione (GSH), the main cellular antioxidant, used by cencer cells to defends themselves from oxidative stress and chemotherapy drugs. The concept to exploit glutamine analogues to kill cancer cells is and old notion of the last entury, since glutamine-like antagonists like azaserine and DON were employed as antineoplastic drugs. However, they are exceedingly toxic and therefore abandoned after the introduction of more selective antitumorals. However, the allurement to kill cancer cells by hitting theri metabolic “core” has been put in reserve among basic scientists. Unable to take advantage of glutamine mimics, the other strategy to use glutamine-deprived preparations has been explored as well, keeping in mind that this aminoacids it pivotal to generate nucleotides for DNA and RNA metabolism.
Scientists gotten pretty good at killing the bulk of cancer cells in leukemias, but a small population of cancer stem cells are uniquely equipped to resist conventional therapies, and these stem cells often survive to restart the condition later. In a recent clinical trial, patients with acute myeloid leukemia who were not candidates for bone marrow transplant were treated with the drug venetoclax, which blocks cells’ ability to uptake aminoacids. In an eariler research, scientists showed that venetoclax associated with another drug, azacytidine is superior to conventional treatments toward leukemic stem cells (LSCs). This combination disrupt energy production in mitochondria in two ways. Firstly interferes with the TCA cycle to produce electrons and organic acids; then triggers the deactivation of the phosphorylative oxidation, the protein cascade that synthesizes ATP, the energy currency. All these disturbances derive form the binding of venetoclax to Bcl-2, the main cellular antiapoptotic protein that mianly resides in mitochondria membranes. These metabolic perturbations efficiently and selectively targets leukemic stem cells (LSCs).
Very basically, leukemia stem cells do not (or are perhaps unable) to switch from cellular respiration to glycolysis like more mature cancer cells. Instead, they switch from metabolizing glucose to metabolizing amino acids – becoming absolutely depend on metabolizing amino acids for energy. The drug venetoclax stops leukemia stem cells from being able to use aminoacids for cellular energy, despite the mechanism is yet not been elucidated. In the lab and now in the clinic, when researchers treated AML patients with venetoclax, leukemia stem cells died. Importantly, because healthy cells do not depend on amino acid metabolism, venetoclax killed leukemia stem cells without harming healthy cells. Interestingly, it was only AML patients who were treated with venetoclax as their first treatment that showed such a dramatic response. When patients were treated with other therapies first, leukemia stem cells were pushed to diversify and some adopted lipid metabolism. When those patients were subsequently treated with venetoclax, the drug killed the cancer stem cells that continued to depend on amino acid metabolism.
On the other side, it was ineffective against cancer stem cells that had switched to lipid metabolism. It was as if lipid metabolism provided an avenue of escape for these cells, and when even a small population of leukemia stem cells was able to resist chemotherapy, they were able to later restart the growth of the disease. Another aminoacid that is under investigation is cysteine, that like glutamine constitues the structure of glutathione. Upon cysteine depletion, leukemic stem cells have tehir glutathione synthesis impaired, leading to reduced glutathionylation of succinate dehydrogenase A, a key enzyme of electron transport chain complex 2. Scientists do not yet know if this cellular signaling is responsible for the switching of glucose to lipid utilization to produce energy. What is clear that cysteine is mainly used by LSCs to make almost exclusively GSH to protect themselves from oxidative stress. This might constitute one major mechamism of drug resistence and escaping apoptosis. This was the reason why arsenic trioxide (ATO) was introduced to counteract drug resistance, since arsenic is a GSH poison and induces reactive oxygen species (ROS).
There is the possibility to interfere also for cystein uptake form cells. Researchers are aware that an old glory among clinical drugs is able to do so. That is salazopyrine, maybe the first drug approved to treat Crohn disease, then rheumatoid arthritis and other bowel inflammatory conditions. Beside scavenging ROS and inhibiting cellular inflammatory cascades (NF-kB), salazopyrine was serendipitously discovered to block xCT/SCL7a11, the membrane transporter for cysteine. There is not yet available data that sulfasalazine acts on leukemic stem cells but it has been proven effective onto lung, bladder, liver and squamous cell carcinoma cells. Scientists are eager to test the possibility that salazopyrine exert these same effects in leukemic stem cells, since the drug is long clinically approved and this way has already accomplished half of the path for repurposing.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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