The Mechanisms Of Anti-asthma Drug Montelukast In Inhibiting Proliferation Of Prostate Cancer Cells

The current costly and time-consuming paradigm of drug discovery is ill-equipped to combat rapidly emerging diseases like cancer.Because existing drugs have known pharmacokinetics and safety profiles,any newly identified use can be rapidly evaluated in phase II clinical trials.To start with an old drug is the most fruitful basis for drug discovery.SENP1 is overexpressed in prostate cancer and promotes the development of prostate cancer.Recently,our studies demonstrated that anti-asthma drug montelukast sodium could inhibit the activity of SENP1 in vitro and the IC₅₀was about 8.7?M.Further studies showed that montelukast sodium could increase the total SUMO level in PC3 cells.Cellular thermal shift assay showed that montleukast could increase the thermal stability of SENP1 in PC3 prostate cancer cells,which indicated the interaction between montelukast and SENP1.We also found that monteluakst downregulated hypoxia and CoCl₂-induced HIF-1?protein and its transcriptional activity.The mRNA level of HIF-1?wasn't influenced by monteluakst.The protein level of its target gene HK-2 was also inhibited by montelukast.The mRNA of other two HIF-1?target genes CA9 and GLUT1 were also downregulated by montelukast.However,the other two leukotriene receptor antagonists pralukast and zafirlukast had no effect on the protein level of HIF-1?.In the presence of proteasome inhibitor MG132 or lysosome inhibitor chloroquine,monteluakst could still inhibit HIF-1?.Further studies demonstrated that montelukast could induce endoplasmic-reticulum stress and increase the phosphorylation of eIF-2?in PC3 and LNCaP prostate cancer cells,demonstrating that montelukast sodium might inhibit the translation of HIF-1?.We concluded that monteluakst might become a drug to treat prostate cancer in future.