Synergistic Antitumor Effects Of Tetrandrine Combination With MS275 In Human Cancer

MS275 has entered the clinical phase ? trial stage for the treatment of leukemia.It inhibits proliferation of tumor cells,promotes apoptosis and prevents tumor migration via activating p21WAFI/CIPI,T?R?,TRAIL and inhibiting Bcl-2,XIAP and other molecules as the class I histone deacetylase inhibitor.MS275 has strong anti-tumor potential in cancer treatment when uses alone,but long-term using of high-dose MS275 will make patients resistant to drugs and generate side effects.We found that the combination with traditional Chinese medicine Tetrandrine and MS275 could significantly induce tumor cell apoptosis,and it had no significant side effects on normal cells.Furthermore,we detected ROS activation during apoptotic processes,and rescued cell death when with the use of ROS scavenger NAC,so we thought that ROS was involved in the regulation of combination of Tetrandrine and MS275 induced apoptosis.In addition,many studies have shown that activation of ROS can lead to oxidative damage to mitochondria which manifests as mitochondrial membrane potential decline and so on.We found that the mitochondrial membrane potential did decrease significantly after treated with the two drugs.Then,we further explored the mechanism of apoptosis induced by two drugs:it was found that Akt expression was up-regulated after the two-drug treatment,but the Akt inhibitor wortmanine did not save the cell death,so we thought that Akt was not involved in the regulation of the apoptosis process.Further study found that the deletion of Bax gene in HCT116 cells tolerated to Tetrandrine combination with MS275 which behaved as increased cell survival,decreased apoptosis,and heterologous expressed of Bax can significantly reverse HCT116 Bax-/-cell resistance.Similar to the process of Bax-induced apoptosis,the p53 gene-deficient HCT116 cell was also insensitive to two drugs.Finally,we used nude mice to construct a tumor xenograft model that was consistent with the results of in vivo cell experiments,that is,Tetrandrine combination with MS275 in vivo could significantly induce tumor cell apoptosis and inhibit tumor growth.Therefore,we found Tetrandrine combined with MS275 had significant synergistic anti-tumor effects both in vivo and in vitro experiments,the discovery will provide a theoretical basis to the combination chemotherapy in clinical application.