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.

The mechanism of FZXJJZ decoction suppresses colorectal liver metastasis via the VDR/TGF-ß/Snail1 signaling pathways based on network pharmacology-TCGA data-transcriptomics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaojijinzhan (FZXJJZF) decoction is an effective prescription for treating colorectal cancer liver metastasis (LMCRC). AIM OF THE STUDY: To elucidate the pharmacological mechanism of the FZXJJZF decoction therapy on LMCRC. MATERIALS AND METHODS: Firstly, a network pharmacological approach was used to characterize the underlying targets of FZXJJZF on LMCRC. Secondly, LMCRC-related genes are obtained from the public database TCGA, and those genes are further screened and clustered through Mfuzz, an R package tool. Then, targets of FZXJJZF predicted by network pharmacology were overlapped with LMCRC related genes screened by Mfuzz. Meanwhile, FZJZXJF intervened in LMCRC model,epithelial-to-mesenchymal transition (EMT), and migration and invasion of HCT-116 cells. Thirdly, the transcriptomics data of FZJZXJF inhibited HCT-116 cells of EMT cells were overlapped with EMT database data to narrow the possible range of targets. Based on this, the potential targets and signal pathways of FZJZXJF were speculated by combining the transcriptomics data with the targets from network pharmacology-TCGA. Finally, the anti-cancer mechanism of FZXJJZF on LMCRC was verified in vitro by Real-Time PCR and Western Blot in vitro. RESULTS: By network pharmacological analysis, 282 ingredients and 429 potential targets of FZXJJZF were predicted. The 9268 LMCRC-related genes in the TCGA database were classified into 10 clusters by the Mfuzz. The two clustering genes with the most similar clustering trends were overlapped with 429 potential targets, and 32 genes were found, such as CD34, TRPV3, PGR, VDR, etc. In vivo experiments, FZJZXJF inhibited the tumor size in LMCRC models, and the EMT, migration, and invasion of HCT-116 also be inhibited. Intersecting transcriptomics dates with 32 target genes, it is speculated that the VDR-TGF-ß signaling pathway may be an effective mechanism of FZXJJZF. Additionally, it is shown that FZXJJZF up-regulated the expression levels of VDR and E-cadherin and down-regulated the expression levels of TGF-ß and Snail1 in vitro. These results confirmed that FZXJJZF plays an effective role in LMCRC mainly by inhibiting EMT phenotype via the VDR-TGF-ß signaling pathway. CONCLUSIONS: Collectively, this study reveals the anti-LMCRC effect of FZXJJZF and its potential therapeutic mechanism from the perspective of potential targets and potential pathways.

Development and Validation of a Nomogram for Predicting Survival in Patients with Advanced Pancreatic Ductal Adenocarcinoma.

This study aimed to develop and validate an effective prognostic nomogram for advanced PDAC patients. We conducted a prospective multicenter cohort study involving 1,526 advanced PDAC patients from three participating hospitals in China between January 1, 2004 and December 31, 2013. Two thirds of the patients were randomly assigned to the training set (n = 1,017), and one third were assigned to the validation set (n = 509). Multivariate cox regression analysis was performed to identify significant prognostic factors for overall survival to develop the nomogram. Internal and external validation using C-index and calibration curve were conducted in the training set and validation set respectively. As results, seven independent prognostic factors were identified: age, tumor stage, tumor size, ALT (alanine aminotransferase), ALB (albumin), CA 19-9, HBV infection status, and these factors were entered into the nomogram. The proposed nomogram showed favorable discrimination and calibration both in the training set and validation set. The C-indexes of the training set and validation set were 0.720 and 0.696 respectively, which were both significantly higher than that of the staging system (C-index = 0.613, P < 0.001). In conclusion, the proposed nomogram may be served as an effective tool for prognostic evaluation of advanced PDAC.

Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: To determine whether the use of radiofrequency ablation (RFA) plus transcatheter arterial chemoembolization (TACE) is more effective than the use of RFA alone for patients with hepatocellular carcinoma (HCC). METHODS: A computer-based search was performed. Randomised trials comparing RFA plus TACE and RFA alone for treatment of HCC were included in this meta-analysis. The outcome of interest for our analysis was survival (recurrence-free survival and overall survival). RESULTS: Eight trials with 648 patients were eligible for this meta-analysis. Our pooled results suggest that RFA plus TACE is associated with a significant advantage in recurrence-free survival (RFS) (HR=0.58; 95% CI=0.42-0.80, P=0.001), and overall survival (OS) (HR=0.60; 95% CI=0.47-0.76, P<0.001). CONCLUSION: TACE combined with RFA was more effective than RFA alone, especially for treatment for intermediate and large-size hepatic tumours or younger patients with HCC.

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.