Research On The Effect And Mechanism Of Sorafenib Against Aspergillus Fumigatus

Background Invasive Aspergillosis(IA)is one of the dominating causes of death in severely immunocompromised individuals.For the past few years,with the prosperous development of bone marrow transplantation as well as solid organ transplantation and the continuous emergence of new-type immunosuppressive agents,the group of immunosuppressive population has kept mounting,and the morbidity of Invasive Aspergillosis(IA)has shown a obvious rising trend.However,the treatment to Invasive Aspergillosis is kind of tough with the extremely limited drug types.At the same time,these drugs also exist plenty of toxic and side effects and there appears resistant strains,it is imperative to explore new-type therapeutic drugs for IA.Aspergillus Fumigatus is the main pathogen cause of IA,accounting for 90%of the total pathogen population.Current drug targets for IA therapy mainly focus on the cell walls as well as cell membranes of aspergillus fumigatus.There has been no drugs targeting the signaling pathway so far.Sorafenib is a new-type anticancer drug that works on signaling pathways,approved by the FDA mostly for the treatment of late liver and kidney cancers.It can constrain signaling pathway of RAF/MEK/ERK which is closely related to cell proliferation in eukaryotic cells.According to previous studies,ERK signaling pathway blocker can inhibit the growth of aspergillus fumigatus This research plans to explore the anti-aspergillus fumigatus effect of sorafenib to make sense of its potential value of anti-aspergillus fumigatusObjective To observe the effect of sorafenib on the growth of Aspergillus fumigatus and detect its anti-aspergillus fumigatus activity in vitro to understand whether sorafenib has anti-aspergillus fumigatus effect.Materials and Methods 1)Inoculate the AF293 aspergillus fumigatus spore suspension into Broth with different sorafenib drug concentrations,and observe the effects brought by the drugs on the Sprouting of aspergillus fumigatus2)Inoculate the AF293 aspergillus fumigatus spore suspension into solid mediums with different sorafenib drug concentrations,and observe the effects brought by the drugs on the radioactive growth of aspergillus fumigatus.3)Reference to M3 8-A2 Broth Dilution method recommended by CLSI(Clinical and Laboratory Standards Institue)to observe the anti-aspergillus fumigatus activity of sorafenib,and its influences on the anti-aspergillus fumigatus activity of several antifungal drugs in vitro.Results According to the results of germination rate of aspergillus fumigatus,1)there the germination time of aspergillus fumigatus in RPMI-1640 Medium?PD liquid medium and SD liquid medium respectively containing 0.5ug/ml,2ug/ml and 8ug/ml,the germination rate of Sorafenib group was lower than that of the normal control group.With the increase of sorafenib concentration,the decrease was more obvious.In RPMI-1640 Medium,8 ug/ml sorafenib group was delayed for about 1 hour compared with the control group.2)While in PDA and SDA medium respectively containing 2ug/ml,8ug/ml,32ug/ml,128ug/ml,aspergillus fumigatus'colony diameter was significantly smaller than that of the control group and was dose-dependent after growing for 24h,48h,72h.3)There is antagonistic effect existing in the combination drug of 64ug/ml and 128ug/ml sorafenib and 2ug/ml and lug/ml ITC,and also in the combination drug sorafenib(16ug/ml,32ug/ml,64ug/ml,128ug/ml)and AMB(1ug/ml and 0.5ug/ml).There is no antagonistic effect produced by the combination drug of sorafenib with voriconazole and caspofunginConclusions Sorafenib has an anti-Aspergillus fumigatus effect.