Study On The Effect And Mechanism Of Arsenic Trioxide Combined With Curcumin On Osteosarcoma

Background Osteosarcoma is a primary malignant osteosarcoma.Preoperative neoadjuvant chemotherapy,surgery and postoperative chemotherapy are the standard treatment for osteosarcoma.However,patients with osteosarcoma are prone to relapse and develop resistance to chemotherapy drugs,resulting in poor prognosis.Arsenic trioxide has been shown to inhibit the progression of osteosarcoma through a variety of signaling pathways,but its clinical application is limited by its potential toxicity.Curcumin is a chemotherapeutic sensitizer and antioxidant commonly used in clinic.The combination of the two drugs may enhance the anti-tumor efficacy and reduce the toxic effects of arsenic trioxide.The present study aimed to investigate the synergistic effect of arsenic trioxide combined with curcumin against osteosarcoma.And further use the network pharmacology analysis to find the key targets of arsenic trioxide combined with curcumin against osteosarcoma,which can provide a new theoretical basis for the drug treatment of osteosarcoma.Methods(1)we treated osteosarcoma cells with different concentrations of curcumin and arsenic trioxide.Cells viability,apoptosis and migration were determined by CCK-8 assay,flow cytometry and scratch test,respectively.(2)The network pharmacological approach was utilized to construct the drug-target-pathway molecular regulatory network for the anti-osteosarcoma effect and resulted in the prediction of the core target.(3)Finally,the combination effect in tumor growth were validated in vivo through osteosarcoma tumor xenografts in BALB/C nude mice.Results(1)After different concentrations of arsenic trioxide and curcumin acted on osteosarcoma cells,the cell proliferation and migration abilities were significantly reduced compared with the control group,and the inhibitory effect was time-and concentration-dependent;Different concentrations of arsenic trioxide and curcumin treated osteosarcoma cells for 48 hours,the m RNA and protein levels of TGFβ1 were significantly decreased.(2)A total of 26 drug-disease intersection targets were screened out.The PPI network found that TGFβ1,STAT3,IL6,MMP2,VEGFA,MAPK1,JUN,TP53,etc.may be key targets.(3)Animal experiments show that arsenic trioxide combined with curcumin can significantly inhibit the growth of osteosarcoma without obvious organ toxicity.Conclusion(1)Our results indicate that curcumin combined with arsenic trioxide can effectively inhibit the proliferation of osteosarcoma and induce tumor cell apoptosis.(2)Drug combination regimens can effectively anti-osteosarcoma while reducing the drug dose of arsenic trioxide and attenuating its toxic effects in vivo experiments.(3)TGFβ1 may be the possible target of curcumin combined with arsenic trioxide against osteosarcoma.