Nobiletin inhibits breast cancer cell migration and invasion by suppressing the IL-6-induced ERK-STAT and JNK-c-JUN pathways.

BACKGROUND: Breast cancer is one of the most common cancers in women, affecting more than 2 million women worldwide annually. However, effective treatments for breast cancer are limited. Nobiletin is a flavonoid present in the dried mature pericarp of mandarin orange (Citrus reticulata Blanco), which is used to prepare Citri Renetulatae Pericarpium and can inhibit tumour growth and progression according to modern pharmacological studies. However, whether nobiletin exhibits an antimetastatic role in breast cancer and its potential mechanism need to be further investigated. PURPOSE: This study aims to evaluate the inhibitory effect of nobiletin on breast cancer and to elucidate potential mechanisms against invasion and migration. METHODS: Cell viability was determined by cell counting kit-8 and colony formation assays. Wound healing and Boyden chamber assays detected cancer cell migration and invasion capabilities. Immunoblotting and qPCR were applied to determine the protein and mRNA expression levels of extracellular signal-regulated kinases (ERK) and the c-Jun N-terminal kinase (JNK) signalling pathways. Molecular docking was used to assess the degree of nobiletin binding to phosphatidylinositol 3-kinase (PI3K). Xenografts and liver metastases were constructed in BALB/c nude mice to evaluate the anticancer effect of nobiletin in vivo. H&E staining and immunohistochemistry were used to detect proliferation and the expression of related proteins. RESULTS: Nobiletin induced cell death in a concentration- and time-dependent manner and possessed anti-invasion and anti-migration effects on MCF-7 and T47D cells by suppressing the interleukin-6-induced ERK and JNK signalling pathways. In addition, nobiletin docked with the binding site of PI3K, and the binding score was -8.0 kcal/mol. Furthermore, the inhibition of breast cancer growth and metastasis by nobiletin was demonstrated by constructing xenografts and liver metastases in vivo. CONCLUSION: Nobiletin inhibited liver metastasis of breast cancer by downregulating the ERK-STAT and JNK-c-JUN pathways, and its safety and efficacy were verified, indicating the potential of nobiletin as an anticancer agent.

Traditional Chinese medicinal herbs combined with epidermal growth factor receptor tyrosine kinase inhibitor for advanced non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeted treatment has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it is not tolerated well by all patients. In China, some studies have reported that traditional Chinese medicinal herbs (TCMHs) may increase efficacy and reduce toxicity when combined with EGFR-TKI, but outside of China few studies of this kind have been attempted. OBJECTIVE: This study is intended to systematically review the existing clinical evidence on TCMHs combined with EGFR-TKI for treatment of advanced NSCLC. SEARCH STRATEGY: PubMed, the Cochrane Library, the Excerpta Medica Database (EMBASE), the China BioMedical Literature (CBM), and the China National Knowledge Infrastructure (CNKI) and web site of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference of Lung Cancer (WCLC) were searched; the search included all documents published in English or Chinese before October 2013. INCLUSION CRITERIA: We selected randomized controlled trials based on specific criteria, the most important of which was that a TCMH plus EGFR-TKI treatment group was compared with an EGFR-TKI control group in patients with advanced NSCLC. DATA EXTRACTION AND ANALYSIS: The modified Jadad scale was used to assess the quality of studies. For each included study, patient characteristics, treatment details, therapeutic approach and clinical outcomes were collected on a standardized form. When disagreements on study inclusion or data extracted from a study emerged, the consensus of all coauthors provided the resolution. The clinical outcome metrics consisted of objective response rate (ORR; complete response + partial response divided by the total number of patients), disease control rate (DCR; complete response + partial response + no change divided by the total number of patients), survival rate, improved or stabilized Karnofsky performance status (KPS), and severe toxicity. RevMan 5.0 software was used for data syntheses and analyses. Risk ratio (RR) and 95% confidence interval (CI) were calculated; if the hypothesis of homogeneity was not rejected (P>0.1, I(2)<50%), the fixed-effect model was used to calculate the summary RR and the 95% CI. Otherwise, a random-effect model was used. RESULTS: In this review, 19 studies were included based on the selection criteria. Of them, 13 studies were of high quality and 6 studies were of low quality, according to the modified Jadad scale. When the TCMH plus EGFR-TKI treatment groups were compared with the EGFR-TKI control groups the meta-analysis demonstrated a statistically significant higher ORR (RR 1.34; 95% CI 1.15 to 1.57; P=0.000 2), DCR (RR 1.18; 95% CI 1.09 to 1.27; P<0.000 1), one-year survival rate (RR 1.21; 95% CI 1.01 to 1.44; P=0.04), 2-year survival rate (RR 1.91; 95% CI 1.26 to 2.89; P=0.002) and improved or stable KPS (RR 1.38; 95% CI 1.26 to 1.51; P<0.000 01). Severe toxicity for rash was decreased (RR 0.55; 95% CI 0.32 to 0.94; P=0.03), as were nausea and vomiting (RR 0.17; 95% CI 0.04 to 0.72; P=0.02) and diarrhea (RR 0.46; 95% CI 0.24 to 0.89; P=0.02). Sensitivity analysis indicated that findings of the meta-analysis were robust to study quality. In the funnel plot analysis, asymmetry was observed, and publication bias was indicated by Egger's test (P=0.03). CONCLUSION: TCMH intervention can increase efficacy and reduce toxicity when combined with EGFR-TKI for advanced NSCLC, although this result requires further verification by more well designed studies.

[Clinical research of intraperitoneal chemotherapy plus Shenmai Injection in treating advanced colorectal cancer].

OBJECTIVE: To study the effects of intraperitoneal chemotherapy (IPC) plus Shenmai Injection (SMI) in treating advanced colorectal cancer following radical resections. METHODS: Fifty-eight cases of colorectal cancer in stage B2 and C following radical resections were divided into two groups: SMI+IPC group (36 cases) and IPC group (22 cases). In the SMI+IPC group, IPC (5-fluorouracil combined with cisplatin) plus SMI was administered, while in the IPC group, only IPC was administered. Clinical symptoms, quality of life (Karnofsky score), white blood cell counts, natural killer cells and CD4/CD8 were observed, and disease-free survival (DFS) rate was also evaluated. RESULTS: The total short-term response rate was 83.33% in the SMI+IPC group, significantly higher than 63.64% in the IPC group (P<0.05). The data of clinical symptoms, quality of life, white blood cell counts, natural killer cells and CD4/CD8 in the SMI+IPC group were also significantly improved as compared with those in the IPC group (P<0.05 or P<0.01). In the SMI+IPC group, 1-, 3- and 5-year DFS rates were 91.7% (33/36), 77.8% (28/36) and 72.2% (26/36) respectively, and those in the IPC group were 90.9% (20/22), 72.7% (16/22) and 45.5% (10/22) respectively. The 5-year DFS rate was significantly improved in the SMI+IPC group as compared with that in the IPC group (P<0.05), while the 1-year and 3-year DFS rates had no significant difference between these two groups. CONCLUSION: IPC plus SMI is effective in treating post-operative patients with advanced colorectal cancer.