背景:化疗耐受性削弱了化疗药物治疗胃癌(GC)的疗效。半夏泻心汤(BXXXD)在中医消化系统疾病中有着数千年的广泛应用。为了更好的处理GC,将其他三种草药添加到BXXXD中,以创建新的处方,称为改良半夏泻心汤(MBXXXD)。尽管MBXXXD可能通过改善化疗耐受性来治疗GC,可能的机制尚不清楚.
目的:探讨MBXXXD对GC患者的治疗作用及可能的抗癌机制。
方法:进行了一项随机对照试验(n=146),以通过测试GC患者的总生存率来评估MBXXXD化疗(n=73)和安慰剂化疗(n=73)之间的临床疗效。无进展生存期,临床症状,生活质量评分,肿瘤标志物,T细胞亚群,和不良反应。进行网络药理学以发现MBXXXD治疗GC的潜在机制。代谢活性测定,在包括AGS细胞在内的人GC细胞系中检测到细胞克隆集落形成和线粒体凋亡,MBXXXD处理的KNM-45细胞和SGC7901细胞。多种途径,包括P53,AKT,IκB,P65,P38,ERK,JNKp-AKT,AGS细胞中的p-P65,p-P38,p-ERK和p-JNK,还检测到MBXXXD处理的KNM-45细胞和SGC7901细胞以及MBXXXD+化疗处理的GC患者。
结果:MBXXXD+化疗促进了总生存期和无进展生存期,改善临床症状和生活质量评分,增加T4淋巴细胞比率和T8淋巴细胞比率以及T4/T8淋巴细胞比率,并减轻GC患者的不良反应。网络药理学预测了MBXXXD治疗GC的多个靶点和途径,包括凋亡,P53通路,AKT通路,MAPK途径。MBXXXD抑制细胞活力,减少细胞克隆集落形成,并通过产生活性氧(ROS)促进线粒体凋亡,在AGS细胞中促进线粒体通透性转换孔(MPTP)和pro-caspase-3和pro-caspase-9的裂解,并减少mito-tracker红色氯甲基-X-氨基胺(CMXRos),KNM-45细胞和SGC7901细胞。MBXXXD上调P53和IκB的表达,下调p-AKT的表达,p-P65,p-P38,p-ERK,p-JNK,AKT,P65,P38,ERK和JNKAGS细胞,MBXXXD治疗的KNM-45细胞和SGC7901细胞以及MBXXXD+化疗治疗的GC患者。
结论:MBXXXD通过调节多种靶点和途径,使GC化疗受益。
BACKGROUND: Chemotherapy tolerance weakened efficacy of chemotherapy drugs in the treating gastric cancer (GC). Banxiaxiexin decoction (BXXXD) was widely used in digestive diseases for thousands of years in Traditional Chinese medicine (TCM). In order to better treat GC, three other herbs were added to BXXXD to create a new prescription named Modified Banxiaxiexin decoction (MBXXXD). Although MBXXXD potentially treated GC by improving chemotherapy tolerance, the possible mechanisms were still unknown.
OBJECTIVE: To explore the therapeutic effect of MBXXXD on GC patients and explore the possible anti-cancer mechanism.
METHODS: A randomized controlled trial (n = 146) was conducted to evaluate the clinical efficacy between MBXXXD + chemotherapy (n = 73) and placebo + chemotherapy (n = 73) in GC patients by testing overall survival, progression free survival, clinical symptoms, quality of life score, tumor markers, T cell subpopulation, and adverse reactions. Network pharmacology was conducted to discover the potential mechanism of MBXXXD in treating GC. Metabolic activity assay, cell clone colony formation and mitochondrial apoptosis were detected in human GC cell lines including AGS cell, KNM-45 cell and SGC7901 cell treated by MBXXXD. Multiple pathways including P53, AKT, IκB, P65, P38, ERK, JNK p-AKT, p-P65, p-P38, p-ERK and p-JNK in AGS cell, KNM-45 cell and SGC7901 cell treated by MBXXXD and GC patients treated by MBXXXD + chemotherapy were also detected.
RESULTS: MBXXXD + chemotherapy promoted overall survival and progression free survival, improved clinical symptoms and quality of life score, increased T4 lymphocyte ratio and T8 lymphocyte ratio as well as T4/T8 lymphocyte ratio, and alleviated adverse reactions in GC patients. Network pharmacology predicted multiple targets and pathways of MBXXXD in treating GC including apoptosis, P53 pathway, AKT pathway, MAPK pathway. MBXXXD inhibited cell viability, decreased cell clone colony formation, and promoted mitochondrial apoptosis by producing reactive oxygen species (ROS), promoting mitochondrial permeability transition pore (MPTP) and the cleavage of pro-caspase-3 and pro-caspase-9, and decreasing mito-tracker red Chloromethyl-X-rosamine (CMXRos) in AGS cell, KNM-45 cell and SGC7901 cell. MBXXXD up-regulated the expression of P53 and IκB, and down-regulated the expression of p-AKT, p-P65, p-P38, p-ERK, p-JNK, AKT, P65, P38, ERK and JNK AGS cell, KNM-45 cell and SGC7901 cell treated by MBXXXD and GC patients treated by MBXXXD + chemotherapy.
CONCLUSIONS: MBXXXD benefitted chemotherapy for GC by regulating multiple targets and pathways.