Amlexanox, an approved anti-inflammatory immunomodulator, has been used for the treatment of allergic rhinitis, bronchial asthma, and allergic conjunctivitis since 1987 in Japan. Its mechanism of action could be associated with the reduction of the release of histamine and leukotrienes from mast cells through its interaction with the cellular protein S100A8. Amlexanox is available worldwide as a 5% topical cream for the treatment of aphthous ulcers of the oral mucosa. In recent years, the possibility that amlexanox can be reused for the treatment of obesity or type 2 diabetes mellitus is likely to generate widespread interest. Administration of amlexanox to obese mice produces reversible weight loss, improves insulin resistance, and reduces metabolic inflammation and hepatic steatosis. Clinical studies have demonstrated the efficacy of amlexanox in a subgroup of diabetic patients with underlying fat inflammation.
Mechanically, the suppressive effect of amlexanox on metabolic inflammation was attributed to its inhibitory action on IKKε / TBK1 protein kinases. A double-blind, randomized clinical trial published in 2017 showed that after 12 weeks of taking amlexanox, a subgroup of patients with type 2 diabetes showed a clinically significant reduction in blood glucose. The results were also confirmed in the following two years. Previous studies had found that these two enzymes are induced in obese mice, causing a drop in energy expenditure or a reduction in calories burned. This prompted the search for inhibitors of these enzymes by screening a chemical library and one of the inhibitors was amexanox. Giving the obese mice the inhibitor made them lose weight, while their insulin sensitivity increased, improving blood sugar and fatty liver (steatosis).
The experiment revealed that the genetic changes that occurred in the mouse model also occurred in human subjects. Blood glucose in clinical trial patients decreased with modification of genes involved in energy expenditure. A biopsy of fat cells from the middle of each patient was taken before and after the study to measure changes in gene expression. One third of the blinded study participants responded. Improvement was also observed among responders with nonalcoholic fatty liver disease. Among one of the molecular mechanisms that has been deciphered very recently there is also the blocking of the enzyme phosphodiesterase 4 (PDE4B) which serves to regulate the cellular concentrations of the second cyclic AMP messenger (cAMP). This enzymatic isoform is also expressed in many other organs and tissue districts.
This suggests that cAMP exerts anti-inflammatory effects mainly by activating its main effector, the protein kinase PKA. Activated PKA can stabilize IκB-alpha, which is the natural inhibitor of the transcription factor NF-κB regulating inflammatory gene expression. The participation of cellular or district inflammation in diabetes is a well recognized aggravating factor on the condition, on the phenomenon of insulin resistance as well as on the onset of late complications. So amlexanox could control inflammation in the diabetic context by targeting the activation of NF-kB operated by different cell signaling pathways. In practice, in tissues where the IKKε / TBK1 pathway prevails, the drug would prefer these enzymes, while in those expressing more PDE4B, the inflammatory reaction could be better controlled with this signaling pathway.
Not surprisingly, the PDE4 antagonist apremilast has a rapid and substantial response for the treatment of aphthous ulcers, which is precisely one of the therapeutic indications of amlexanox. In 2019, a group of researchers from the Department of Neurology at Hebei University in China found that treating mice with classical experimental models of multiple sclerosis (EAE) responded well to the administration of amlexanox. The drug prevented the maturation of dendritic cells derived from the bone marrow and recluated by the nervous system to present the antigen to T lymphocytes. Also in this case, amlexanox worked as an inhibitor of the IKKε // TBK1 protein kinases. The drug significantly attenuated the development of encephalomyelitis by decreasing inflammatory infiltration and demyelination in the spinal cord, accompanied by a reduced frequency of pathogenic Th1 and Th17 lymphocytes and an increase in Treg lymphocytes.
The drug potently reduced the activities of IRF3 and AKT, both substrates of TBK1 and associated with dendritic cell maturation. But the surprises are not over. This extremely versatile molecule appears to have molecular targets that could redirect it in the treatment of other common human diseases. In 2020, a Japanese research group from the University of Kyushu was studying the protein kinase GRK5 in the context of cartilage cell degeneration. By analyzing samples of normal tissue and from mice and patients with osteoarthritis, the research team was able to ascertain that the protein kinase GRK5 was more expressed in diseased cartilage tissues, where it drove cellular catabolism and reinforced gene expression guided once again by the NF-kB factor. By genetically removing the GRK5 protein, the chondrocytes were more vital and less stressed, an effect that was also obtained by treating the cells and sick animals with amlexanox.
In this cellular context, the scientists saw that the drug is also a relatively selective inhibitor of the protein kinase GRK5. This extends the list of cellular targets of this extraordinary molecule which is also capable of interfering with lipoxygenase enzymes (5-LOX and 12-LOX), and calcium-dependent cellular proteins (S100A4, S100A6) widely implicated in asthmatic manifestations. The last frontier is that of the scientific community which is trying to bring substantial evidence that allows the use of this safe and well-known drug in the fight against cancer. Although amlexanox may be inhibitory on the proliferation of malignant cells through the PDE4-PKA and IKK / TBK1 / NF-kB pathways, its potency as a single agent was found to be modest. Instead, it becomes much more active when combined with certain chemo drugs (docetaxel, TMZ) or biotherapeutic agents (anti-PD-1 and anti-CTLA4 antibodies). We’ll see which tricks this “poker face” still has in store.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
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