Montelukast Performs Synergistic Effect with Carfilzomib in Multiple Myeloma by Inhibiting the Deubiquitinase UCHL1

Abstract

Immunomodulators play an important role in combination chemotherapy of multiple myeloma. Besides, it has been reported that leukotriene-D4 receptors play an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (both an immunomodulator and a CysLT1R antagonist) both in single and in combination with carfilzomib in multiple myeloma cells and the potential mechanisms. We performed our experiment using cell apoptosis assay, cell cycle assay, western blot analysis, mitochondrial transmembrane potential, and chemical proteomics based on protein activity. The results showed that montelukast inhibits cell proliferation and leads to cell apoptosis in multiple myeloma cell lines. Then we performed combination of montelukast and carfilzomib on multiple myeloma cells to explore whether they are synergistic. We demonstrated that the combination treatment leads to stronger effect of cell apoptosis. Furthermore, we demonstrated the combination effect is performed independent of the leukotriene-D4 receptors inhibition. Given that protesome inhibitor leads to accumulation of ubiquitin by inhibiting the degradation of these proteins, we tested ubiquitin levels of different groups. We found that montelukast induces ubiquitin accumulation by inhibiting Ubiquitin-Specific Protease UCHL1. All of these lead to the activity of indoplasmic reticulum stress and therefore result in cell apoptosis. This brings us a new idea in the treatment of multiple myeloma. Since montelukast is cheap and widely used in clinic, if it is proved to be effective in the treatment of multiple myeloma, it will greatly reduce the economic pressure of patients and bring new hope to patients.