| Cancer is one of the biggest problems facing humanity today,and the development of anticancer drugs has never stopped.Traditional anticancer drug development has the characteristics of high cost,long time consumption and low success rate.It is a do-over process thatincluding the identification and validation of new molecular entities.Despite significant investments in drug discovery and development over the past few decades and explosive advances in biotechnology/information technology,there has been no significant increase in the number of new drugs entering the clinic.The huge demand for new anticancer drugs is unsatisfactory for the development of traditional new molecular entity drugs.Exploring from existing non-anticancer drugs to discover their anticancer effects will provide an opportunity for treatment options to rapidly advance to clinical trials.This is a process of repositioning the drug,which is the new use of old drugs.The most famous example is thalidomide,which is a great pity for serious fetal teratogenic side effects.However,the study found that its teratogenic mechanism involves inhibition of angiogenesis and DNA damage,making the drug approved by the FDA for the treatment of multiple myeloma.The anti-tumor effect of the drug selected in this study was unexpectedly discovered when treating a cancer patient with trypanosomiasis.Nifurtimox is an anti-parasitic drug used in South America for the treatment of trypanosomiasis.It has been used for nearly half a century.Nifurtimox is one of the two anti-cancer drugs with high clinical efficacy.Chagas disease,also known as American trypanosomiasis,is an infectious disease caused by T.cruzi infection.There are two possible mechanisms for the treatment of Chagas disease by Nifurtimox.One is the formation of Nitro anions by Nifurtimox,and the other is involved in the production of superoxide anion.In this study,the antitumor effect of Nifurrtimox and its preliminary mechanism were studied in vivo and in vitro.In this study,in vitro anti-tumor growth experiments,it was found that Nifurtimox could effectively inhibit the growth of SH-SY5 Y,NCI-H460,KCC853,Hep G2 and K562 cells,with IC50 of 35.3±2.2?M,47.2±3.1?M,59.0±6.5?M,70.9±3.9?M,92.9±4.8 ?M,respectively.Theinfluence of Nifurtimox on the apoptosis rate of five kinds of cells was detected by flow cytometry.The results showed that Nifurtimox could significantly induce apoptosis of SH-SY5 Y,NCI-H460 and KCC853 cells in vitro,and the apoptosis rate reached 13.78~52.02% at 50?M.DNA damage of Nifurtimox on five tumor cells was observed by comet electrophoresis.Flow cytometry was used to detect the ROS expression level in tumor cells,indicating that Nifurtimox could significantly induce the ROS expression of five kinds of cells in vitro,and the expression of SOD and GPx was also detected to be increased.The results of in vitro experiments showed that Nifurtimox had good therapeutic effects on the five kinds of cells tested.Through animal experiments,SH-SY5Y-luc2-GFP and NCI-H460-luc2-GFP cells transfected with p CDH-luc2-GFP were used.The results showed that Nifurtimox could effectively inhibit the growth of SH-SY5 Y renal metastatic tumor and NCI-H460 brain metastatic tumor.The disease progression,physical deterioration and survival rate of tumor-bearing nude mice were slowed down.In summary,the antitumor activity of Nifurtimox has been confirmed.By increasing intracellular ROS level,Nifurtimox can damage DNA and induce apoptosis of SH-SY5 Y,NCI-H460,KCC853,Hep G2 and K562 cells. |
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