The Investigation Of CT-1042 On Anti-tumor Pharmacodynamics And Evaluation With The Combination Of Curcumin

CT-1042(4-Ethyl-8-fluoro-4-hydroxy-9-methoxy-11-methyl-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione),a small molecular compound,exhibited potent anti-tumor activities against many tissue-derived tumor cells in vitro experiments.The incidence of non-small cell lung cancer(NSCLC)is high and the consequences are serious.Although targeted drugs have been marketed,they are susceptible to drug resistance and the population is limited.The development of new anti-lung cancer drugs is still an urgent clinical need.CT-1042 is a novel camptothecin compound with strong anti-cancer activity,but its role and underlying mechanism for lung cancer cells is unclear.In this study,while systematically evaluating the anti-cancer characteristics of CT-1042,the anticancer properties and molecular mechanisms of CT-1042 on NCI-H460 NSCLC cells were evaluated and studied.Here,MTT assay was performed to evaluate cell proliferation activity,along with flow cytometry for apoptosis and mitochondrial membrane potential(MMP)and cell cycle analysis.Real-time quantitative PCR and Western blotting was conducted to determine the relative mRNA and protein expression level.Tumor xenograft experiment was performed to evaluate the effect of CT-1042 on tumor growth in vivo.We demonstrated that CT-1042 obviously inhibited proliferation of the thirteen cancer cells,induced the decrease of MMP in subject cells,and increased the activity of Caspase-3.Cell cycle analysis indicated CT-1042 delayed cell cycle progression in G2/M phase in a dose-dependent effect.In addition,CT-1042 induced mitochondrial mediated apoptosis by activation of p53 and Bax,inhibition of Bcl-2 and Survivin.Finally,CT-1042 significantly suppressed the growth of NCI-H460 xenograft tumor in vivo,and it has higher safety and lower toxicity under current dosing regimen.Collectively,CT-1042 has a significant anti-lung cancer activity that promises to become a new and highly effective anticancer drug.Furthermore,the causes of most refractory diseases,such as cancer,have very complex causes,involving multiple targets,multiple links,and it may be effective only if it is treated for multiple targets.However,the development of new drugs with a single structure that target multiple targets simultaneously is a difficult task.Therefore,the combination of new drugs has actually become the mainstream of disease treatment and an important direction of drug development.In this study,curcumin and CT-1042 were used in combination to evaluate their anti-tumor effects on human lung cancer cells and their molecular mechanisms.The synergistic effects and antagonism were calculated quantitatively using the “One Belt & One Line Method” discovered and named by our group.The results showed that the combination of CT-1042 and Curcumin presented an additive or synergistic effect in vitro and in vivo,and exerted a combined anti-tumor effect by inducing cell cycle arrest and inducing apoptosis through the mitochondrial pathway.So,this method is suitable for the quantitative calculation of the additive effects of multiple drugs including two,three,four and more drugs.