A new study has found a link between lactate metabolism and cholesterol regulation in canine hemangiosarcoma, and shown that combining a statin with dipyridamole delayed tumour growth in mouse models.
The study looked at lactate dehydrogenase (LDH) in canine HSA. Endothelial cells, the type of cell that HSA arises from, rely heavily on glycolysis for energy, even when oxygen is available. This led the researchers to ask whether LDH, an enzyme involved in lactate production, plays a role in HSA biology.
Using two canine HSA cell lines, the researchers blocked LDH with two different compounds. Both approaches slowed cell growth and reduced histone lactylation, a process where lactate attaches to proteins that package DNA, affecting which genes get turned on. When they looked at the genes that were affected, they found that cholesterol and fat metabolism genes were among the most impacted. This was unexpected, as LDH is usually associated with sugar metabolism.
The effect varied between the two cell lines. In one, one inhibitor worked better; in the other, a different inhibitor had a stronger effect. This suggests that HSA tumours are biologically diverse: what works for one tumour may not work the same way for another.
To explore this further, the researchers deleted the genes that produce the two parts of LDH—LDHA and LDHB—in one of the cell lines. Removing LDHA consistently reduced cholesterol-related gene activity and SREBP2 protein levels. Removing LDHB also reduced SREBP2 and lipid droplets, but the effects were less consistent. This suggests that while LDHA plays a bigger role, both parts contribute to cholesterol production.
The researchers suggest two possible explanations for how LDH affects cholesterol. First, blocking LDH may shift the balance of NADH and NAD+ inside the cell, which can slow down other metabolic pathways and reduce the signals that turn on cholesterol production. Second, lower lactate levels may reduce histone lactylation, which could affect how cholesterol-related genes are expressed.
Because statins (which lower cholesterol) have shown mixed results in human cancers due to a feedback loop that can limit their effectiveness, the researchers tested fluvastatin alone and in combination with dipyridamole, a drug that helps block that feedback loop.
In the lab, fluvastatin slowed HSA cell growth. But when they tested it in mice with HSA tumours, fluvastatin alone didn’t do much. However, when they combined fluvastatin with dipyridamole, the tumours grew more slowly.
The combination didn’t shrink tumours, it just slowed them down. But the researchers point out that in canine HSA, where cancer often spreads before it’s even diagnosed, slowing progression could still be valuable alongside standard treatment.
The authors caution that the drug doses used were relatively high, and further studies are needed to determine whether this combination would work in actual dogs, at what dose, and with what side effects. They also note that their findings are based on only two cell lines and two mouse models, so more research is needed to confirm the results.
Still, the study provides a rationale for further investigation. If confirmed in clinical trials, a statin-dipyridamole combination could offer a new, relatively inexpensive, and well-tolerated way to help manage canine HSA.
