| Background: Cancer has become one of the leading causes of death in many countries around the world.lt is expected that the number of cancer patients will further increase in the coming decades.Currently,chemotherapeutic strategy is the primary treatment for many tumors.However,with the large-scale application of chemotherapy drugs in clinic,side-effects and resistance substantially limit the efficacy,resulting in a poor prognosis.Therefore,more research is urgently needed to identify new therapeutic targets and protocols to alleviate the limitations of current conventional chemotherapy.Recently,it has been manifested that combined treatment of two or more agents may significantly enhance the therapeutic efficacy of the single component through a synergistic effect,with lowtoxicity and high-effective abilities.GZD824,a small-molecule targeted agent,has been proved to be a new inhibitor with a better therapeutic effect of reversing imatinib resistance in hematologic tumors,but the specific roles and mechanism of GZD824 in other multidrug-resistant tumors have not been elucidated.The present study was to evaluate the antitumor effects of GZD824,a small molecule tyrosinase inhibitor,combined with paclitaxel on the multidrug-resistant tumors in vitro and in vivo.Objective:To investigate the anti-tumor activity and the underlying mechanisms of GZD824 combined with paclitaxel on multidrug-resistant tumors in vitro and in vivo.Methods: 1.The anti-proliferation effect was assessed by colony formation assay,cell viability,cell apoptosis and cell cycle assay.The anti-tumor efficacy in vivo was evaluated in nude mice with Bats72 xenografts.2.Flow cytometry analysis and western blot were used to detect the expression and functional changes of p-gp and FEN1 in multi-drugs resistant cancer cells treated with GZD824 and paclitaxel.Results: 1.In the SNU449,HCT116 and MD-MBA-468 tumor cells,the proliferation inhibition rates of paclitaxel monotherapy group were 8.86%,11.89% and 5.52%,respectively,while the proliferation inhibition rates of GZD824 combined with paclitaxel treatment group were 72.85%,67.22% and 75.82%,respectively.The results showed that GZD824 in combination with Paclitaxel could synergically kill a variety of tumor cells.Meanwhile,GZD824 combined with paclitaxel effectively reverse drug resistance of Bats72 cells to paclitaxel,docetaxel and cabazitaxel,and the reversal coefficient(IR)were 6.62,5.14 and 7.7 times,respectively.2.The flow cytometry analysis results showed that compared with paclitaxel monotherapy group,GZD824 combined with paclitaxel treatment group increased the proportion of blocked cells in G2/M phase of cell cycle from 16.4% to 74.5% and the apoptosis rate increased from 6.81% to 46.1%,indicating that GZD824 combined with paclitaxel treatment group had significantly higher cell cycle G2/M stage arrest and cell apoptosis rate.3.Xenograft tumor model test in nude mice showed that co-administration of GZD824 and paclitaxel group had a significantly greater inhibition in tumor growth than the paclitaxel monotherapy group,with a tumor inhibition rate of 84.6%.Meanwhile,no significant weight loss was observed in the mice.4.As revealed by Western blot assay,there was no significantly change in the expression and function of drug resistance related proteins p-gp.But the combination of GZD824 with paclitaxel significantly down-regulated the expression of FEN1.Conclusion: 1.GZD824 combined with paclitaxel can effectively inhibit the proliferation of multiple tumor cells and reverse cancer multi-drug resistance,which may be bridged by the cell cycle arrest in G2/M phase and cell apoptosis.2.Co-administration of GZD824 and paclitaxel showed a significant anti-tumor effect in vivo,with low-toxicity and high-effective abilities,indicating a better application prospect.3.The synergistic antitumor activity of GZD824 and paclitaxel on multidrug-resistant tumors may be achieved by down-regulating the expression of FEN1 instead of relying on affecting the expression and function of p-gp pathway. |
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