Studies On The Effect And Mechanism Of Extracts And Active Compounds Of Glycyrrhiza Uralensis On Doxorubicin-induced Cardiotoxicity

Doxorubicin is a highly effective antineoplastic agent against many malignant diseases.Its clinical use,unfortunately,must be limited due to its undesirable serious cardiotoxicity.It had been proved that extracts of licorice(Glycyrrhiza uralensis) could prevent acute cardiactoxicity induced by doxorubicin.However,the effect of the extracts on doxorubicin-induced chronic cardiactoxicity and the active ingredient were still not clear.Research studies involving in the problems mentioned above were presented as below.To assess the effect of extracts of licorice on doxorubicin-induced chronic cardiactoxicity,weight,survival rate,the changes of cardiac histopathological and myocardial ultrastructure,activities of succinate dehydrogenase and cytochrome c oxidase,reactive oxygen species concentration,lipid peroxidation and high-energy phosphate levels were measured.The results showed that licorice extracts alleviated doxorubicin-induced chronic cardiactoxicity through protecting the structures of myocardial tissue and mitochondria,maintaining mitochondrial function and improving energy metabolism.H9c2 cells were used to evaluate the protective effect of 23 licorice compounds against doxorubicin-induced cytotoxicity.Six structurally similar compounds were selected to investigate their abilities to scavenging superoxide anion radical and effect on the efficiency of doxorubicin on tumor cells.And then the relationship between biological activities and chemical structures was discussed.The results showed that chalcones possessed stronger activity to scavenging superoxide anion radical and protective effect on doxorubicin-induced cytotoxicity than flavanones.While 4'-OH of a chalcone was substituted by apiose-glucoside,the activities mentioned above were disappear.Moreover,the changes also decrease the efficiency of doxorubicin on tumor cells.This study evaluated the effects of isoliquiritin and liquiritin on doxorubicin-induced apoptosis.Hoechst 33342 staining and TUNEL assay were used to measure the apoptotic rate.Western-blotting was used to detect the expression of apoptosis-related proteins Bcl-xl and Bax.Fluorescent assay was used to determine the activities of caspase-8 and caspase-3 and the level of intracellular reactive oxygen species.The results showed that isoliquiritin and liquiritin both inhibited doxorubicin-induced H9c2 cells apoptosis and did not affect its anti-tumor activity,in which isoliquiritin might play a protective effect through mitochondrial and non-mitochondrial pathways.Taken together,extracts of licorice could maintain mitochondrial structure and function,alleviated doxorubicin-induced chronic cardiactoxicity.A variety of flavonoid compounds of licorice showed a direct protective effect on myocardial cells,in which the activities of chalcones were stronger than flavanones.Isoliquiritin and liquiritin,two typical flavonoids of licorice,inhibited doxorubicin-induced H9c2 cells apoptosis through different pathways.This study provided new scientific evidences on using licorice,a traditional Chinese herb,to prevent doxorubicin-induced cardiactoxicity.