| ObjectiveLung cancer is the leading course of mortality in oncology. Non-small-cell lung cancer(NSCLC) is the major part of the lung cancer and most of the NSCLC patients were advanced when diagnosized. Patients with EGFR ge ne-non mutation or EGFR mutation are treated with chemotherapy based on platinum or epidermal growth factor receptor tyrosine kinased inhibitor (EGFR-TKI)respectively. Only30%of all the NSCLC patients who harboring the EGFR mutation have the opportunity of benefiting from EGFR-TKI while EGFR-TKI is an oral drug with less toxity. Even though, patients who are s ensitive to EGFR-TKI have a mean PFS of11months.For a long time, using Chinese medicine as a treatment of non-small cell lung cancer has its own unique theory and methodology. It can be us ed alone to make the tumor smller than befor. It can give thepatients Ion g-term survival. Reduce chemotherapy side effects, improve patient treatm ent effects and prolong patients survival. There are so many clinical and basic experimental study has been reported in patients using chemotherap y combined with TCM. But weather the Chinese medicine in the treatment o f advanced non-small cell lung cancer patients is better than the using o f gefitinib alone or not has no answer. We speculate that combination of EGFR-TKI and FZKA freeze dried powder would be a useful strategy for pa tients who are resistant to EGFR-TKI.1Evaluated systematically the studies of traditional Chinese medicin e combined with gefitinib in the treatment of advanced non-small cell lun g cancer were in order to provide the feasibility of documentary evidence of FuzhengKangai decoction combined with gefitinib in the treatment of p atients with non small cell lung cancer.2Study of three kinds of NSCLC cell lines (A549, H1650, PC9) for dru g sensitivity test and related signaling pathways, observation the effect and discover the mechanism of the combination of Fuzhengkangai Decoction and Gifitinib in the singaling pathways in three different kinds of cel l linesMethods1We searched the National Digital Library Federation (http://www.ucdrs.n et/admin/union/index.do)(2006-2012)、CNKI(2006-2012)、VIP (2006-2012).Two re viewers independtly evaluated the quality of the included studies and ext racted the data. Meta-analyses were performed by RevMan4.0software.2Cells were exposed to gefitinib, FZKA freeze dried powder or the co mbination and the effects of inhibition were analyzed with MTT assay and flow cytometry.3Observing response of signaling pathway moleculars with the methods of western blotting.ResultsNine randomized controlled trials (RCTs) involving528patients were included. The results of meta-analysis showed that:the combination group s howed remarkable advantage in disease control rate、the improvement of KPS, decreased diarrhea, no improvement of liver function damage, the decreased nausea and vomiting.Cell lines were divided into gefitinib sensitive group and gefitinib resistant group by the OD value of MTT. ONE WAY ANOVA analysis was used t o analyze the inhinbit rates of different cells with the same treatment. Factor analysis was used to analyze the inhibit rates of different treatm ent in the same cell line.For the gefitinib-resitant cell lines:A549and H1650, there are sigini ficant difference was observed between A549and H1650when using the same dose of gefitinib. F=7.57, P=0.0101. gefitinib make a superiority effect in A549to H1650.For the three cell lines, fzka freeze dried powder make more remarkab le inhibit effects to A549than the other two cell lines(F=9.23, P=0.000 The combination group make more remarkable apatosis effects in three cells lines than the single drug used. A549(12.6333±4.47698)%, H1650(25.4667±20.6011)%,(26.8333±10.4357)%.By the methods of western blotting, in the dose-response experiments of FZKA to intevent the A549, P-EGFR, EZH2showed a dose-dependent decline, PPAR-gomma and P53showed a dose-dependent rise, in the dose-response e xperiments of FZKA to intevent the H1650, EZH2showed the dose-dependent downward trend, suggesting that FZKA make the H1650has a positive protei n expression, For the P-EGFR, no dose-dependent trend showed. When the dr ug concentration reaches a certain level, P-EGFR expression will go down. PPAR-gomma and P53showed no dose-dependent rise, p=0.000in the stati stical analysis of the results, in the dose-response experiments of FZKA to intevent the PC9, EZH2showed the dose-dependent downward trend, FZKA has a positive regulating effection to EZH2expression of PC9. And betwee n the different doses, statistical analysis, p=0.0000. For the P-EGFR, showed no dose-dependent manner, when the drug concentration reaches a c ertain level, P-EGFR expression will go down. PPAR-gomma and P53showed a dose-dependent rise, statistical analysis of the results between differ ent doses of p=0.000, with statistical significance, The FZKA can inter vent the protein expression of PC9showed a positive trend when the dru g’concentration reaches a certain level.In the dose-response experiments of FZKA to intevent the A549P-erk r endered good time correlation between different time points and the stati stical analysis showed:p=0.0036, Its has statistical significance. In the dose-response experiments of FZKA to intevent the H1650, P-AKT, P-er k, P-P38showed good time correlation between the different time points a nd the statistical analysis showed p=0.0000, p=0.0130, p=0.000, Th e data showed statistical significance. In the dose-response experiments of FZKA to intevent the PC9, P-AKT, P-P38showed good time correlation b etween different time points and statistical analysis p=0.0000, p=0.0046, with statistical significance.The FZKA’s singal effect to P-EGFR of A549, F value is90.31. P=0.0000. The Gifitinib’s singal effect to P-EGFR of A549,49, F value is70.44, P=0,00The combination effect F value is8.32, P=0.0204. These date indicate that the two singal drug both has effect to the expression of P-EGFR. When these two drugs use together, they can make more significant influence to the expression of P-EGFR. The FZKA’s singal effect to EZH2of A549, F value is49.66,p=0.000. The Gifitinib’s singal effect to EZH2of A549, F value is55.17, P=0.0000. The combination effect F value is1.69. P=0.2293. These date indicate that the two singal drug both has effect to the expression of EZH2. When these two drugs use together, they can make more significant influence to the expression of EZH2. The FZKA’s singal effect to ppar-gamma of A549, F value is2.96, P=0.000. The Gifitinib’s singal effect to ppar-gamma of A549, F value is31.95, P=0.000. The combination effect F value is2.83.P=0.1311. These date indicate that Gifitinib has effect to the expression of ppar-gamma and FZKA has no effect to it. When these two drugs use together, they can make significant influence to the expression of ppar-gamma. The FZKA’s singal effect to P53of A549, F value is80.63, P=0.000. The Gifitinib’s singal effect to P53of A549, F value is2.04,P=0.1913, The combination effect F value is26.77.P=0.0008. These date indicate that FZKA has up regulation effect to the expression of P53and Gifitinib has down regulation effect. When these two drugs used together, they can make more significant influence to the expression of P53. The FZKA’s singal effect to P-AKT of A549, F value is8.97, P=0.0172. The Gifitinib’s singal effect to P-AKT of A549, F value is34.10, P=0.0004. The combination effect F value is8.09. P=0.0217. These date indicate that the two singal drug both has effect to the expression of P-AKT. When these two drugs use together, they can make more significant influence to the expression of P-AKT. The FZKA’s singal effect to P-erk of A549, F value is1.43, P=0.2654, The Gifitinib’s singal effect to P-erk of A549, F value is22.22, P=0.0015. The combination effect F value is3.72. P=0.0898. These date indicate that Gifitinib has up regulation effect to the expression of P-erk and FZKA has no effect. When these two drugs used together, they can make more significant influence to the expression of P-erk. The FZKA’s singal effect to P-P38of A549, F value is8.66, P=0.0186, The Gifitinib’s singal effect to P-P38of A549, F value is29.58, P=0.0006. The combination effect F value is0.97. P=0.3544. These date indicate that Gifitinib and FZKA both has up regulation effect to the expression of P-P38When these two drugs used together, they can make more significant influence to the expression of P-P38.The FZKA’s singal effect to P-EGFR of H1650, F value is3.84. P=0.0855. The Gifitinib’s singal effect to P-EGFR of H1650,, F value is6.01, P=0.0399The combination effect F value is3.00, P=0.1217. These date indicate that the two singal drug both has down regulate effect to the expression of P-EGFR. When these two drugs use together, they can make more significant influence to the expression of P-EGFR. The FZKA’s singal effect to EZH2of H1650, F value is89.93. P=0.0000. The Gifitinib’s singal effect to EZH2of H1650,, F value is152.01, P=0.0000. The combination effect F value is22.58, P=0.0014. These date indicate that the two singal drug both has down regulate effect to the expression of EZH2. When these two drugs use together, they can make more significant influence to the expression of EZH2. The FZKA’s singal effect to ppar-gomma of H1650, F value is8.97.P=0.0172. The Gifitinib’s singal effect to ppar-gomma of H1650,,F value is25.96, P=0.0172. The combination effect F value is25.96, P=0.0009. These date indicate that Gifitinib has up regulate effect to the expression of ppar-gomma. When these two drugs use together, they can make more significant influence to the expression of ppar-gomma. The FZKA’s singal effect to P53of H1650, F value is17.71.P=0.0030. The Gifitinib’s singal effect to P53of H1650,,F value is25.66, P=0.0010. The combination effect F value is1.65, P=0.2353. These date indicate that these two drugs both has up regulate effect to the expression of P53. When these two drugs use together,they can make more significant influence to the expression of P53. The FZKA’s singal effect to P-AKT of H1650, F value is44.61. P=0.0002. The Gifitinib’s singal effect to P-AKT of H1650,, F value is2.75, P=0.1358. The combination effect F value is6.90, P=0.0.0303. These date indicate that these two drugs both has down regulate effect to the expression of P-AKT. When these two drugs use together,they can make more significant influence to the expression of P-AKT. The FZKA’s singal effect to p-erk of H1650, F value is5.50. P=0.0471. The Gifitinib’s singal effect to p-erk of H1650,, F value is10.08, P=0.0131. The combination effect F value is10.19, P=0.0128. These date indicate that Gifitinib has up regulate effect to the expression of p-erk. When these two drugs use together,they can make more significant influence to the expression of p-erk. The FZKA’s singal effect to P-P38of H1650, F value is309.69. P=0.0000. The Gifitinib’s singal effect to P-P38of H1650,, F value is118.04, P=0.0000. The combination effect F value is3.92, P=0.0832. These date indicate that Gifitinib has up regulate effect to the expression of P-P38. When these two drugs use together, they can make more significant influence to the expression of P-P38. The FZKA’s singal effect to P-EGFR of PC9, F value is4.42. P=0.0686.The Gifitinib’s singal effect to P-EGFR of A549,49, F value is675.00, P=0.0000The combination effect F value is1.47, P=0.2598. These date indicate that the two singal drug both has effect to the expression of P-EGFR. When these two drugs use together, they can make more significant influence to the expression of P-EGFR. The FZKA’s singal effect to EZH2of PC9,F value is127.48. P=0.0000. The Gifitinib’s singal effect to EZH2of PC9, F value is242.55, P=0.0000The combination effect F value is6.86, P=0.0307. These date indicate that the two singal drug both has effect to the expression of EZH2. When these two drugs use together, they can make more significant influence to the expression of EZH2. The FZKA’s singal effect to ppar-gomma of PC9, F value is7.90. P=0.0228. The Gifitinib’s singal effect to ppar-gomma of PC9, F value is14.59, P=0.0051The combination effect F value is2.16, P=0.1800. These date indicate that the Gifitinib has the up regulate effect of ppar-gomma. When these two drugs use together, they can make more significant influence to the expression of ppar-gomma. The FZKA’s singal effect to P53of PC9, F value is12.95. P=0.0070. The Gifitinib’s singal effect to P53of PC9, F value is49.45, P=0.0001The combination effect F value is1.76, P=0.2208. These date indicate that the Gifitinib has the up regulate effect of P53. When these two drugs use together, they can make more significant influence to the expression of P53. The FZKA’s singal effect to P-AKT of PC9, F value is3.31. P=0.1066. The Gifitinib’s singal effect to P-AKT of PC9, F value is33.39, P=0.0004The combination effect F value is7.02, P=0.0293. These date indicate that the Gifitinib has the most significant down regulate effect to the expression of P-AKT. The FZKA’s singal effect to P-erk of PC9, F value is23.06. P=0.0014. The Gifitinib’s singal effect to P-erk of PC9, F value is53.75, P=0.0001The combination effect F value is4.77, P=0.0605. These date indicate that the Gifitinib has the most significant up regulate effect to the expression of P-erk. The FZKA’s singal effect to P-P38of PC9, F value is0.04. P=0.8530. The Gifitinib’s singal effect to P-P38of PC9, F value is17.38, P=0.0031The combination effect F value is29.24, P=0.0006. These date indicate that the two singal drug both has effect to the expression of P-P38. When these two drugs use together, they can make more significant influence to the expression of P-P38.Conclusion The present clinical study results suggest the cobination of TCM and gefitinib shows more superiority for non-small cell lung cancer, and its c linical application is worthy to be advocated.The combination treatment of geitinib and the Chinese medicine powder achieved dose dependent enhanced apatosis effects. For A549cell, the Chi nese powder alone showed stonger inhibit effencicy than the other two cel l lines.The combination treatment could effectively inhibit P-EGFR and EZH2t hrough inhibit the P13K/akt and RAS/Raf/MAPK/ERK pathway. |
PDF Full Text Request